Aminoguanidines and alkoxyguanidines as protease inhibitors

ABSTRACT

Aminoguanidine and alkoxyguanidine compounds, including compounds of the formula:                    
     wherein X is O or NR 9  and R 1 14 R 4 , R 6 -R 9 , R 11 , R 12 , R a , R b , R c , Y, Z, n and mare set forth in the specification, as well as hydrates, solvates or pharmaceutically acceptable salts thereof, that inhibit proteolytic enzymes such as thrombin are described. Also described are methods for preparing the compounds of Formula I. The novel compounds of the present invention are potent inhibitors of proteases, especially trypsin-like serine proteases, such as chymotrypsin, trypsin, thrombin, plasmin and factor Xa. Certain of the compounds exhibit antithrombotic activity via direct, selective inhibition of thrombin, or are intermediates useful for forming compounds having antithrombotic activity. The invention includes a composition for inhibiting loss of blood platelets, inhibiting formation of blood platelet aggregates, inhibiting formation of fibrin, inhibiting thrombus formation, and inhibiting embolus formation in a mammal, comprising a compound of the invention in a pharmaceutically acceptable carrier. Other uses of compounds of the invention are as anticoagulants either embedded in or physically linked to materials used in the manufacture of devices used in blood collection, blood circulation, and blood storage, such as catheters, blood dialysis machines, blood collection syringes and tubes, blood lines and stents.

This application claims benefit under 35 U.S.C. § 119(e) of U.S.Provisional Application No. 60/031,822, filed Nov. 26, 1996, thecontents of which are fully incorporated by reference herein.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel compounds that finction as enzymeinhibitors, and particularly to a new class of non-peptidic inhibitorsof proteolytic enzymes.

2. Related Art

Proteases are enzymes that cleave proteins at single, specific peptidebonds. Proteases can be classified into four generic classes: serine,thiol or cysteinyl, acid or aspartyl, and metalloproteases (Cuypers etal., J Biol. Chem. 257:7086 (1982)). Proteases are essential to avariety of biological activities, such as digestion, formation anddissolution of blood clots, reproduction and the immune reaction toforeign cells and organisms. Aberrant proteolysis is associated with anumber of disease states in man and other mammals. The human neutrophilproteases, elastase and cathepsin G, have been implicated ascontributing to disease states marked by tissue destruction. Thesedisease states include emphysema, rheumatoid arthritis, corneal ulcersand glomerular nephritis. (Barret, in Enzyme Inhibitors as Drugs,Sandler, ed., University Park Press, Baltimore, (1980)). Additionalproteases such as plasmin, C-1 esterase, C-3 convertase, urokinase,plasminogen activator, acrosin, and kallikreins play key roles in normalbiological functions of mammals. In many instances, it is beneficial todisrupt the function of one or more proteolytic enzymes in the course oftherapeutically treating a mammal.

Serine proteases include such enzymes as elastase (human leukocyte),cathepsin G, plasmin, C-1 esterase, C-3 convertase, urokinase,plasminogen activator, acrosin, chymotrypsin, trypsin, thrombin, factorXa and kallikreins.

Human leukocyte elastase is released by polymorphonuclear leukocytes atsites of inflammation and thus is a contributing cause for a number ofdisease states. Cathepsin G is another human neutrophil serine protease.Compounds with the ability to inhibit the activity of these enzymes areexpected to have an anti-inflammatory effect useful in the treatment ofgout, rheumatoid arthritis and other inflammatory diseases, and in thetreatment of emphysema. Chymotrypsin and trypsin are digestive enzymes.Inhibitors of these enzymes are useful in treating pancreatitis.Inhibitors of urokinase and plasminogen activator are useful in treatingexcessive cell growth disease states, such as benign prostatichypertrophy, prostatic carcinoma and psoriasis.

The serine protease thrombin occupies a central role in hemostasis andthrombosis, and as a multifactorial protein, induces a number of effectson platelets, endothelial cells, smooth muscle cells, leukocytes, theheart, and neurons (Tapparelli et al., Trends in PharmacologicalSciences 14:366-376 (1993); Lefkovits and Topol, Circulation90(3):1522-1536 (1994); Harker, Blood Coagulation and Fibrinolysis 5(Suppl 1):S47-S58 (1994)). Activation of the coagulation cascade througheither the intrinsic pathway (contact activation) or the extrinsicpathway (activation by exposure of plasma to a non-endothelial surface,damage to vessel walls or tissue factor release) leads to a series ofbiochemical events that converge on thrombin. Thrombin cleavesfibrinogen ultimately leading to a hemostatic plug (clot formation),potently activates platelets through a unique proteolytic cleavage ofthe cell surface thrombin receptor (Coughlin, Seminars in Hematology31(4):270-277 (1994)), and autoamplifies its own production through afeedback mechanism. Thus, inhibitors of thrombin function havetherapeutic potential in a host of cardiovascular and non-cardiovasculardiseases, including: myocardial infarction; unstable angina; stroke;restenosis; deep vein thrombosis; disseminated intravascular coagulationcaused by trauma, sepsis or tumor metastasis; hemodialysis;cardiopulmonary bypass surgery; adult respiratory distress syndrome;endotoxic shock; rheumatoid arthritis; ulcerative colitis; induration;metastasis; hypercoagulability during chemotherapy; Alzheimer's disease;Down's syndrome; fibrin formation in the eye; and wound healing. Otheruses include the use of said thrombin inhibitors as anticoagulantseither embedded in or physically linked to materials used in themanufacture of devices used in blood collection, blood circulation, andblood storage, such as catheters, blood dialysis machines, bloodcollection syringes and tubes, blood lines and stents.

Factor Xa is another serine protease in the coagulation pathway. FactorXa associates with factor Va and calcium on a phospholipid membranethereby forming a prothrombinase complex. This prothrombinase complexthen converts prothrombin to thrombin (Claeson, Blood Coagulation andFibrinolysis 5:411-436 (1994); Harker, Blood Coagulation andFibrinolysis 5 (Suppl 1):S47-S58 (1994)). Inhibitors of factor Xa arethought to offer an advantage over agents that directly inhibit thrombinsince direct thrombin inhibitors still permit significant new thrombingeneration (Lefkovits and Topol, Circulation 90(3):1522-1536 (1994);Harker, Blood Coagulation and Fibrinolysis 5 (Suppl 1):S47-S58 (1994)).

A need continues to exist for non-peptidic compounds that are potent andselective protease inhibitors, and which possess greater bioavailabilityand fewer side-effects than currently available protease inhibitors.Accordingly, new classes of potent protease inhibitors, characterized bypotent inhibitory capacity and low mammalian toxicity, are potentiallyvaluable therapeutic agents for a variety of conditions, includingtreatment of a number of mammalian proteolytic disease states.

Ozawa, H. et al., Yakugaku Zasshi, 95(8):966-74 (1975) describe a numberof benzyl- and benzylidine aminoguanidine and amidinohydrazonecompounds. For example, the following salts are described:

The compounds were tested for their effect on blood pressure in rats.

Augstein, J. et al.,” J Med. Chem., 10(3):391-400 (1967) discloses aseries of aryloxyalkylamino-guanidines of the formula:

In some compounds R₁ is methoxy, while R₂ is hydrogen and R₃ and R₄ areeither hydrogen or methyl. Several such aminoguanidines containingchloro and methyl substituents in the aromatic ring were shown topossess adrenergic neuron blocking properties and to inhibit dopamineβ-oxidase in vitro. The synthesis and testing of aminoguanidinescontaining one or more methoxy substituents in the aromatic ring is alsodisclosed.

SUMMARY OF THE INVENTION

The present invention is directed to novel compounds having Formula I(below). Also provided are processes for preparing compounds of FormulaL The novel compounds of the present invention are potent inhibitors ofproteases, especially trypsin-like serine proteases, such aschymotrypsin, trypsin, thrombin, plasmin and factor Xa. Certain of thecompounds exhibit antithrombotic activity via direct, selectiveinhibition of thrombin, or are intermediates useful for formingcompounds having antithrombotic activity.

The invention includes a composition for inhibiting loss of bloodplatelets, inhibiting formation of blood platelet aggregates, inhibitingformation of fibrin, inhibiting thrombus formation, and inhibitingembolus formation in a mammal, comprising a compound of the invention ina pharmaceutically acceptable carrier. These compositions may optionallyinclude anticoagulants, antiplatelet agents, and thrombolytic agents.The compositions can be added to blood, blood products, or mammalianorgans in order to effect the desired inhibitions.

Also provided are methods of inhibiting or treating aberrant proteolysisin a mammal, and methods for treating myocardial infarction; unstableangina; stroke; restenosis; deep vein thrombosis; disseminatedintravascular coagulation caused by trauma, sepsis or tumor metastasis;hemodialysis; cardiopulmonary bypass surgery; adult respiratory distresssyndrome; endotoxic shock; rheumatoid arthritis; ulcerative colitis;induration; metastasis; hypercoagulability during chemotherapy;Alzheimer's disease; Down's syndrome; fibrin formation in the eye; andwound healing. Other uses of compounds of the invention are asanticoagulants either embedded in or physically linked to materials usedin the manufacture of devices used in blood collection, bloodcirculation, and blood storage, such as catheters, blood dialysismachines, blood collection syringes and tubes, blood lines and stents.

The invention also includes a method for reducing the thrombogenicity ofa surface in a mammal by attaching to the surface, either covalently ornoncovalently, a compound of the invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Compounds of the present invention include compounds of Formula I:

or a solvant, hydrate or pharmaceutically acceptable salt thereof;wherein;

R¹ is one of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl orheteroaryl, any of which may be optionally substituted;

Z is one of —NR¹⁰SO₂—, —SO₂NR¹⁰—, —NR¹⁰C(R^(y)R^(z))—,—C(R^(y)R^(z))NR¹⁰—, —OSO₂—, —SO₂O—, —OC(R^(y)R^(z))—, —C(R^(y)R^(z))O—,—NR¹⁰CO— or —CONR¹⁰—;

R^(y) and R^(z) are each independently one of hydrogen, alkyl,cycloalkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl,monoalkylaminoalkyl, dialkylaminoalkyl or carboxy;

R², R³ and R⁴ are each independently one of hydrogen, alkyl, cycloalkyl,alkenyl, alkynyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heteroaryl, trifluoromethyl, halogen,hydroxyalkyl, cyano, nitro, carboxamido, —CO₂R^(x), —CH₂OR^(x) or—OR^(x), or when present on adjacent carbon atoms, R² and R³ may also betaken together to form one of —CH═CH—CH═CH— or —(CH₂)_(q)—, where q isfrom 2 to 6, and R⁴ is defined as above;

R^(x), in each instance, is independently one of hydrogen, alkyl orcycloalkyl wherein said alkyl or cycloalkyl groups may optionally haveone or more unsaturations;

Y is one of —O—, —NR¹⁰—, —S—, —CHR¹⁰— or a covalent bond;

X is oxygen or NR⁹;

R⁹ is one of hydrogen, alkyl, cycloalkyl or aryl, wherein said alkyl,cycloalkyl or aryl can be optionally substituted with amino,monoalkylamino, dialkylamino, alkoxy, hydroxy, carboxy, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, aryl, heteroaryl, acylamino, cyano ortrifluoromethyl;

R⁶ is one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl,monoalkylamino(C₂₋₁₀)alkyl, dialkylamino(C₂₋₁₀)alkyl or carboxyalkyl, oralternatively, R⁶ and R¹² taken together to form —(CH₂)_(w)—, where w is1-5;

R⁷ is one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl,monoalkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, hydroxy, alkoxy,aralkoxy, aryloxy, heteroaryloxy, or mono- or di-alkylamino, providedthat n is other than zero when R⁷ is hydroxy, alkoxy, aralkoxy, aryloxy,heteroaryloxy, or mono- or di-alkylamino;

R⁸, R¹¹ and R¹² are each independently one of hydrogen, alkyl, aralkyl,aryl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkylor carboxyalkyl;

or R⁷ and R⁸ are taken together to form —(CH₂)_(y)—, where y is zero (abond), 1 or 2, while R¹¹ and R¹² are defined as above; or R⁷ and R¹² aretaken together to form —(CH₂)_(q)—, where q is zero (a bond), or 1 to 8,while R⁵ and R¹¹ are defined as above; or R₈ and R¹¹ are taken togetherto form —(CH₂)_(r)—, where r is 2-8, while R⁷ and R¹² are defined asabove;

R¹⁰, in each instance, is independently one of hydrogen, alkyl, aralkyl,aryl, hydroxy(C₂₋₁₀)alkyl, amino(C₂₋₁₀)alkyl,monoalkylamino(C₂₋₁₀)alkyl, dialkylamino(C₂₋₁₀)alkyl or carboxyalkyl;

R^(a), R^(b) and R^(c) are independently hydrogen, alkyl, hydroxy,alkoxy, aryloxy, aralkoxy, alkoxycarbonyloxy, cyano or —CO₂R^(w);

R^(w) is alkyl, cycloalkyl, phenyl, benzyl,

where R^(d) and R^(e) are independently hydrogen, C₁₋₆ alkyl, C₂₋₆alkenyl or phenyl, R^(f) is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl orphenyl, R^(g) is hydrogen, C,₁₋₆ alkyl, C₂₋₆ alkenyl or phenyl, andR^(h) is aralkyl or C₁₋₆ alkyl;

n is from zero to 8; and m is from zero to 4.

A preferred group of compounds falling within the scope of the presentinvention include compounds of Formula I wherein:

R¹ is one of C₆₋₁₀ aryl, pyridinyl, thiophenyl (i.e., thiophene),quinazolinyl, quinolinyl or tetrahydroquinolinyl, any of which isoptionally substituted by one or two of hydroxy, nitro, trifluoromethyl,halogen, C₁₋₆ alkyl, C₆₋₁₀ aryl, C₁₋₆ alkoxy, C₆₋₁₀ ar(C₁₋₆)alkoxy, C₁₋₆aminoalkyl, C₁₋₆ aminoalkoxy, amino, mono(C₁₋₄)alkylamino,di(C₁₋₄)alkylamino, C₂₋₆ alkoxycarbonylamino, C₂₋₆ alkoxycarbonyl,carboxy, C₁₋₆ hydroxyalkyl, C₂₋₆ hydroxyalkoxy,(C₁₋₆)alkoxy(C₂₋₆)alkoxy, mono- and di- C₁₋₄ alkylamino(C₂₋₆)alkoxy,C₂₋₁₀ mono(carboxyalkyl)amino, di(C₂₋₁₀ carboxyalkyl)amino, C₆₋₁₄ar(C₁₋₆)alkoxycarbonyl, C₂₋₆ alkynylcarbonyl, C₁₋₆ alkylsulfonyl, C₂₋₆alkenylsulfonyl, C₂₋₆ alkynylsulfonyl, C₆₋₁₀ arylsulfonyl, C₆₋₁₀ar(C₁₋₆)alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonamido, C₆₋₁₀arylsulfonamido, C₆₋₁₀ ar(C₁₋₆)alkylsulfonamido, amidino, guanidino,C₁₋₆ alkyliminoamino, formyliminoamino, C₂₋₆ carboxyalkoxy, C₂₋₆carboxyalkyl, carboxyalkylamino, cyano, trifluoromethoxy,perfluoroethoxy and R¹³R¹⁴NSO₂—;

R¹³ and R¹⁴ are independently selected from the group consisting ofhydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl,heterocycle, heterocycloalkyl, carboxyalkyl, alkoxycarbonylalkyl,cyano(C₂₋₁₀)alkyl, hydroxy(C₂₋₁₀)alkyl, alkoxy(C₂₋₁₀)alkyl, mono- anddi-alkylamino(C₂₋₁₀)alkyl, or R¹³ and R¹⁴ can be taken together with thenitrogen atom to which they are attached to form a three to sevenmembered ring, optionally containing one or more heteroatoms in additionto said nitrogen, such as oxygen, sulfur, or nitrogen (NR¹⁵), said ringbeing preferably saturated, and said ring having one or two optionalsubstituents selected from the group consisting of hydroxy, acyloxy,alkoxy, aryloxy, amino, mono- and di-alkylamino, acylamino, alkyl,cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycle,heterocycloalkyl, carboxyalkyl, alkoxycarbonylalkyl, cyano(C₂₋₁₀)alkyl,hydroxy(C₂₋₁₀)alkyl, alkoxy(C₂₋₁₀)alkyl, mono- anddi-alkylamino(C₂₋₁₀)alkyl, carboxy, alkoxycarbonyl, carboxamido, formyl,alkanoyl, aroyl, aralkanoyl, sulfonyl, alkylsulfonyl, alkoxysulfonyl,sulfonamido, phosphonyl, phosphoramido, and phosphinyl, and wherein R¹⁵is selected from the group consisting of hydrogen, alkyl, cycloalkyl,alkenyl, alkynyl, aryl, aralkyl, heterocycle, heterocycloalkyl,carboxyalkyl, alkoxycarbonylalkyl, cyano(C₂₋₁₀)alkyl,hydroxy(C₂₋₁₀)alkyl, alkoxy(C₂₋₁₀)alkyl, mono- anddi-alkylamino(C₂₋₁₀)alkyl, carboxy, alkoxycarbonyl, carboxamido, formyl,alkanoyl, aroyl, aralkanoyl, sulfonyl, alkylsulfonyl, alkoxysulfonyl,sulfonamido, phosphonyl, phosphoramido, and phosphinyl;

Z is one of —SO₂O—, —SO₂NR¹⁰—, —C(R^(y)R^(z))O— or —OC(R^(y)R^(z))—,where R^(y) and R^(z) are each hydrogen;

R², R³ and R⁴ are independently one of hydrogen, C₁₋₄ alkyl, C₃₋₈cycloalkyl, phenyl, benzyl, trifluoromethyl, halogen,hydroxy(C₁₋₄)alkyl, cyano, nitro, carboxamido, carboxy, C₁₋₄alkoxycarbonyl, C₁₋₄ alkoxymethyl or C₁₋₄ alkoxy; or alternatively, R²and R³, when present on adjacent carbon atoms, may also be takentogether to form one of —CH═CH—CH═CH— or —CH₂)_(q)—, where q is from 2to 6, and R⁴ is as defined above;

Y is one of —O—, —S—, —NR¹⁰—, or a covalent bond;

R^(a), R^(b) and R^(c) are each one of hydrogen, C₁₋₄ alkyl, hydroxy,C₁₋₄ alkoxy, phenoxy, C₁₋₄ alkyloxycarbonyl, benzyloxycarbonyl, cyano,

where

R^(h) is benzyl, methyl, ethyl, isopropyl, sec-butyl or t-butyl, andwhere R^(f) is hydrogen a or C₁₋₆ alkyl;

R⁶ is one of hydrogen, C₁₋₆ alkyl, C₆₋₁₀ ar(C₁₋₆)alkyl, C₆₋₁₀ aryl,C₂₋₁₀ hydroxyalkyl, C₂₋₁₀ aminoalkyl, mono(C₁₋₄)alkylamino(C₂₋₈)alkyl,di(C₁₋₄)alkylamino(C₂₋₈)alkyl or C₂₋₁₀ carboxyalkyl;

R⁷, R⁸, R¹¹ and R¹² are independently one of hydrogen, C₁₋₆ alkyl, C₂₋₁₀carboxyalkyl or C₂₋₁₀ hydroxyalkyl, or R⁷ and R⁸ are taken together toform —(CH₂)_(y)— where y is zero, 1 or 2, while R¹¹ and R¹² are definedas above; or R⁷ and R¹² are taken together to form —(CH₂)_(q)—, where qis zero (a bond), or 1, 2 or 3, while R⁸ and R¹¹ are defined as above;or R⁸ and R¹¹ are taken together to form —(CH₂)_(r)—, where r is 2, 3,or 4, while R⁷ and R¹² are defined as above;

R⁹ is hydrogen, or C₁₋₁₀ alkyl, optionally substituted with amino,mono(C₁₋₄)alkylamino, C₁₋₆ alkoxy, hydroxy, carboxy, phenyl, C₁₋₄alkyloxycarbonyl, C₆₋₁₀ ar(C₁₋₄)alkoxycarbonyl, C₁₋₆ acylamino, cyano ortrifluoromethyl;

R¹⁰, in each instance, is independently hydrogen, C₁₋₆ alkyl, benzyl,phenyl, C₂₋₁₀ hydroxyalkyl, C₂₋₁₀ aminoalkyl, C₁₋₄monoalkylamino(C₂₋₈)alkyl, C₁₋₄ dialkylamino(C₂₋₈)alkyl or C₂₋₁₀carboxyalkyl;

n is from zero to 8; and m is from zero to 4.

In this preferred embodiment, R¹ can be one of C₆₋₁₀ aryl, pyridinyl,thiophenyl (i.e., thiophene), quinazolinyl, quinolinyl ortetrahydroquinolinyl, any of which is optionally substituted by one ortwo of hydroxy, nitro trifluoromethyl, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₆ aminoalkyl, C₁₋₆ aminoalkoxy, amino, mono(C₁₋₄)alkylamino,di(C₁₋₄)alkylamino, C₂₋₆ alkoxycarbonylamino, C₂₋₆ alkoxycarbonyl,carboxy, C₁₋₆ hydroxyalkyl, C₂₋₆ hydroxyalkoxy, C₂₋₁₀mono(carboxyalkyl)amino, bis(C₂₋₁₀ carboxyalkyl)amino, C₆₋₁₄ar(C₁₋₆)alkoxycarbonyl, C₂₋₆ alkynylcarbonyl, C₁₋₆ alkylsulfonyl, C₂₋₆alkenylsulfonyl, C₂₋₆ alkynylsulfonyl, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonamido, amidino, guanidino, C₁₋₆ alkyliminoamino,formyliminoamino, C₂₋₆ carboxyalkoxy, C₂₋₆ carboxyalkyl,carboxyalkylamino, cyano, trifluromethoxy, and perfluoroethoxy.

An especially preferred group of compounds include compounds of FormulaI wherein:

R¹ is one of phenyl, naphthyl, pyridyl, thiophenyl, quinolinyl orisoquinolinyl, optionally substituted by one or two of chloro, methoxy,methyl, trifluoromethyl, cyano, nitro, amino or dimethylamino;

Z is one of —SO₂O—, —SO₂NR¹⁰—, —CH₂O— or —OCH₂—;

R² and R³ are hydrogen or C₁₋₄ alkyl, or R² and R³ may also be takentogether to form —CH═CH—CH═CH—;

R⁴ is one of hydrogen, methyl, methoxy or trifluoromethyl;

Y is one of O, NR¹⁰ or a covalent bond;

R^(a), R^(b) and R^(c) are hydrogen, hydroxy,

where

R^(h) is benzyl or t-butyl, and where R^(f) is hydrogen or methyl;

R⁶ is hydrogen, C₁₋₄ alkyl, C₂₋₄ hydroxyalkyl, C₂₋₄ carboxyalkyl, C₂₋₄aminoalkyl, dimethylamino(C₂₋₈)alkyl, or methylamino(C₂₋₈)alkyl;

R⁷, R⁸, R¹¹ and R¹² are independently one of hydrogen, C₁₋₆ alkyl, C₂₋₁₀hydroxyalkyl or C₂₋₁₀ carboxyalkyl, or R⁷ and R⁸ are taken together toform —(CH₂)_(y)— where y is zero, 1 or 2, while R¹¹ and R¹² are definedas above; or R⁷ and R¹² are taken together to form —(CH₂)_(q)—, where qis zero (a bond), or 1, 2 or 3, while R⁸ and R¹¹ are defined as above;or R⁸ and R¹¹ are taken together to form —(CH₂)_(r)—, where r is 2, 3 or4, while R⁷ and R¹² are defined as above;

R⁹ is hydrogen or C₁₋₄ alkyl;

R¹⁰, in each instance, is independently hydrogen, C₁₋₄ alkyl, C₂₋₄hydroxyalkyl, C₂₋₄ carboxyalkyl, C₂₋₄ aminoalkyl,dimethylamino(C₂₋₈)alkyl, methylamino(C₂₋₈)alkyl;

n is from zero to 4; and m is zero, 1, 2 or 3.

Another especially preferred group of compounds include compounds ofFormula I wherein:

R¹ is phenyl, substituted by one of alkylsulfonyl, arylsulfonyl andR¹³R¹⁴NSO₂—, where R¹³ and R¹⁴ are independently selected from the groupconsisting of hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₆₋₁₀ ar(C₁₋₄)alkyl, pyridyl, pyridyl(C₁₋₄)alkyl,carboxy(C₁₋₆)alkyl, C₁₋₄ alkoxycarbonyl(C₁₋₄)alkyl, cyano(C₂₋₆)alkyl,hydroxy(C₂₋₆)alkyl, C₁₋₄ alkoxy(C₂₋₆)alkyl, mono- anddi-(C₁₋₄)alkylamino(C₂₋₆)alkyl, or R¹³ and R¹⁴ can be taken togetherwith the nitrogen atom to which they are attached to form a heterocyclicring selected from the group consisting of N-morpholinosulfonyl,N-piperazinylsulfonyl (optionally N′ substituted with C₁₋₆ alkyl, C₁₋₆hydroxyalkyl, C₆₋₁₀ aryl, C₆₋₁₀ aryl(C₁₋₆)alkyl, C₁₋₆ alkylsulfonyl,C₆₋₁₀ arylsulfonyl, C₁₋₆ alkylcarbonyl, morpholino or C₆₋₁₀arylcarbonyl), N-pyrrolylsulfonyl, N-piperidinylsulfonyl,N-pyrrolidinylsulfonyl, N-dihydropyridylsulfonyl, N-indolysufonyl,wherein said heterocyclic ring can be optionally substituted with one ortwo of hydroxy, C₁₋₈ alkanoyloxy, C₁₋₆ alkoxy, C₆₋₁₀ aryloxy, amino,mono- and di- C₁₋₆ alkylamino, C₁₋₈ alkanoylamino, C₁₋₄ alkyl, C₃₋₇cycloalkyl, C₆₋₁₀ aryl, C₆₋₁₀ ar(C₁₋₄)alkyl, heterocycle,heterocycloalkyl, carboxy(C₁₋₆)alkyl, C₁₋₄ alkoxycarbonyl(C₁₋₄)alkyl,cyano(C₂₋₆)alkyl, hydroxy(C₂₋₆)alkyl, C₁₋₄ alkoxy(C₂₋₆)alkyl, mono- anddi-(C₁₋₄)alkylamino(C₂₋₆)alkyl, carboxy, C₁₋₆ alkoxycarbonyl,carboxamido, formyl, C₁₋₆ alkanoyl, C₆₋₁₀ aroyl, C₆₋₁₀ ar(C₁₋₄)alkanoyl,sulfonyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkoxysulfonyl, sulfonamido,

Z is one of —SO₂—, —SO₂NR¹⁰—, —CH₂O— or —OCH₂—;

R² and R³ are hydrogen or C₁₋₄ alkyl, or R² and R³ may also be takentogether to form —CH═CH—CH═CH—;

R⁴ is one of hydrogen, methyl, methoxy or trifluoromethyl;

Y is one of O, NR¹⁰ or a covalent bond;

R^(a), R^(b) and R^(c) are hydrogen, hydroxy,

where

R^(h) is benzyl or t-butyl, and where R^(f) is hydrogen or methyl;

R⁶ is hydrogen, C₁₋₄ alkyl, C₂₋₄ hydroxyalkyl, C₂₋₄ carboxyalkyl, C₂₋₄aminoalkyl, dimethylamino(C₂₋₈)alkyl, or methylamino(C₂₋₈)alkyl;

R⁷, R⁸, R¹¹ and R¹² are independently one of hydrogen, C₁₋₆ alkyl, C₂₋₁₀hydroxyalkyl or C₂₋₁₀ carboxyalkyl, or R⁷ and R⁸ are taken together toform —(CH₂)_(y)— where y is zero, 1 or 2, while R¹¹ and R¹² are definedar above; or R⁷ and R¹² are taken together to form —(CH₂)_(q)—, where qis zero (a bond), or 1, 2 or 3, while R⁸ and R¹¹ are defined as above;or R⁸ and R¹¹ are taken together to form —(CH₂)_(r)—, where r is 2, 3 or4, while R⁷ and R¹² are defined above;

R⁹ is hydrogen or C₁₋₄ alkyl;

R¹⁰, in each instance, is independently hydrogen, C₁₋₄ alkyl, C₂₋₄hydroxyalkyl, C₂₋₄ carboxyalkyl, C₂₋₄ aminoalkyl,dimethylamino(C₂₋₈)alkyl, methylamino(C₂₋₈)alkyl;

n is from zero to 4; and m is zero, 1, 2 or 3.

The moiety —Z—R¹ of Formula I is attached to the benzene ring in aposition ortho-, meta- or para- to Y, with the meta-position beingpreferred.

Preferred compounds of the present invention are those of Formula Iwherein Y is one of divalent oxygen (—O—), —NR¹⁰— or a covalent bond,most preferably —O— and Z is one of —SO₂NR¹⁰—, —SO₂— or —CH₂—, mostpreferably —SO₂O—.

Preferred compounds of the present invention are those of Formula Iwherein R¹ is one of C₁₋₁₂ alkyl, especially C₃₋₈ alkyl, C₄₋₇cycloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl or C₆₋₁₄ aryl, especially C₆₋₁₀aryl, any of which is optionally substituted. Substituents that can beoptionally present on the R¹ moieties include one or more, preferablyone or two, of hydroxy, nitro, trifluoromethyl, halogen, alkoxy,aralkoxy, aminoalkoxy, aminoalkyl, hydroxyalkyl, hydroxyalkoxy,alkoxyalkoxy, mono- and di-alkylaminoalkoxy, cyano, aryl, amino,monoalkylamino, dialkylamino, carboxy, carboxyalkyl, carboxyalkoxy,mono(hydroxyalkyl)amino, bis(hydroxyalkyl)amino,mono(carboxyalkyl)amino, bis(carboxyalkyl)amino, alkoxycarbonylamino,alkoxycarbonyl, aralkoxycarbonyl, alkenylcarbonyl, alkynylcarbonyl,alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl,aralkylsulfonyl, alkylsulfinyl, alkylsulfonamido, arylsulfonamido,aralkylsulfonamido, amidino, guanidino, alkyliminoamino,formyliminoamino, trifluoromethoxy, perfluoroethoxy or an aminosulfonylgroup R¹³R¹⁴NSO₂—, where R¹³ and R¹⁴ are as defined above. A furthersubstituent on aryl, cycloalkyl, alkenyl, alkynyl and aralkyl moietiesof R¹ includes one or more, preferably one or two, alkyl moieties.

Preferred values of optional substituents on R¹ include hydroxy, nitro,trifluoromethyl, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ aminoalkyl,C₆₋₁₀ aryl, C₆₋₁₀ ar(C₁₋₆)alkoxy, biphenyl(C₁₋₆)alkoxy C₁₋₆ aminoalkoxy,amino, mono(C₁₋₄)alkylamino, di(C₁₋₄)alkylamino, C₂₋₆alkoxycarbonylamino, C₂₋₆ alkoxycarbonyl, carboxy, C₁₋₆ hydroxyalkyl,C₂₋₁₀ mono(carboxyalkyl)amino, bis(C₂₋₁₀ carboxyalkyl)amino, C₆₋₄ar(C₁₋₆)alkoxycarbonyl, C₂₋₆ alkynylcarbonyl, C₁₋₆ alkylsulfonyl, C₆₋₁₀arylsulfonyl, C₂₋₆ alkenylsulfonyl, C₂₋₆ alkynylsulfonyl, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonamido, amidino, guanidino, C₁₋₆alkyliminoamino, formyliminoamino, C₂₋₆ carboxyalkoxy,carboxyalkylamino, cyano, trifluoromethoxy, and perfluoroethoxy.

Additional preferred values of optional substituents on R¹ include C₁₋₆alkylsulfonyl, C₆₋₁₀ arylsulfonyl, C₆₋₁₀ ar(C₁₋₆)alkylsulfonyl, C₆₋₁₀arylsulfonamido, C₆₋₁₀ ar(C₁₋₆)alkylsulfonamido, N-morpholinosulfonyl,and R¹³R¹⁴NSO₂—, where R¹³ and cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₆₋₁₀ ar(C₁₋₄)alkyl, pyridyl, pyridyl(C₁₋₄)alkyl,carboxy(C₁₋₆)alkyl, C₁₋₄ alkoxycarbonyl(C₁₋₄)alkyl, cyano(C₂₋₆)alkyl,hydroxy(C₂₋₆)alkyl, C₁₋₄ alkoxy(C₂₋₆)alkyl, mono- anddi-(C₁₋₄)alkylamino(C₂₋₆)alkyl, or R¹³ and R¹⁴ can be taken togetherwith the nitrogen atom to which they are attached to form a heterocyclicring selected from the group consisting of N-morpholinosulfonyl,N-piperazinylsulfonyl (optionally N′ substituted with C₁₋₆ alkyl, C₁₋₆hydroxyalkyl, C₆₋₁₀ aryl, C₆₋₁₀ aryl(C₁₋₆)alkyl, C₁₋₆ alkylsulfonyl,C₆₋₁₀ arylsulfonyl, C₁₋₆ alkylcarbonyl, morpholino or C₆₋₁₀arylcarbonyl), N-pyrrolylsulfonyl, N-piperidinylsulfonyl,N-pyrrolidinylsulfonyl, N-dihydropyridylsulfonyl, N-indolylsufonyl,wherein said heterocyclic ring can be optionally substituted with one ortwo of hydroxy, C₁₋₈ alkanoyloxy, C₁₋₆ alkoxy, C₆₋₁₀ aryloxy, amino,mono- and di- C₁₋₆ alkylamino, C₁₋₈ alkanoylamino, C₁₋₄ alkyl, C₃₋₇cycloalkyl, C₆₋₁₀ aryl, C₆₋₁₀ ar(C₁₋₄)alkyl, heterocycle,heterocycloalkyl, carboxy(C₁₋₆)alkyl, C₁₋₄ alkoxycarbonyl(C₁₋₄)alkyl,cyano(C₂₋₆)alkyl, hydroxy(C₂₋₆)alkyl, C₁₋₄ alkoxy(C₂₋₆)alkyl, mono- ordi-(C₁₋₄)alkylamino(C₂₋₆)alkyl, carboxy, C₁₋₆ alkoxycarbonyl,carboxamido, formyl, C₁₋₆ alkanoyl, C₆₋₁₀ aroyl, C₆₋₁₀ ar(C₁₋₄)alkanoyl,sulfonyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkoxysulfonyl, sulfonamido,phosphonyl, phosphoramido, or phosphinyl.

An additional preferred group of compounds are those compounds ofFormula I wherein R¹ is heteroaryl or substituted heteroaryl. PreferredR¹ heteroaryl groups include pyridyl, pyrazolyl, thiophenyl, chromenyl,benzoxazolyl, benzthiadiazolyl, quinazolinyl, quinolinyl, isoquinolinyland tetrahydroquinolinyl, with thiophenyl, quinazolinyl quinolinyl andtetrahydroquinolinyl being more preferred and thiophenyl, isoquinolinyland quinolinyl especially preferred. Preferred compounds when R¹ issubstituted heteroaryl include those compounds having one of theheteroaryl groups mentioned as preferred that have one or more,preferably one or two, substituents that are listed in the precedingparagraph. Preferred substituents when R¹ is substituted heteroarylinclude one or more substituents, preferably 1 to 3 substituents,independently selected from halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, amidino,guanidino, carboxyalkoxy, carboxyalkylamino, amino, mono(C₁₋₆)alkylaminoand/or di(C₁₋₆)alkylamino.

Useful values of R¹ include phenyl, chlorophenyl, iodophenyl,dichlorophenyl, bromophenyl, trifluoromethylphenyl,methylsulfonylphenyl, di(trifluoromethyl)phenyl, methylphenyl,t-butylphenyl, methoxyphenyl, dimethoxyphenyl, hydroxyphenyl,carboxyphenyl, aminophenyl, methylaminophenyl, n-butylminophenyl,amidinophenyl, guanidinophenyl, formyliminoaminophenyl,acetimidoylaminophenyl, methoxycarbonylphenyl, ethoxycarbonylphenyl,carboxymethoxyphenyl, naphthyl, hydroxynaphthyl, cyclohexyl,cyclopentyl, 2-propylbutyl, 5-chloro-2-methoxyphenyl, 2-cyanophenyl,2-(N-hydroxy)aminophenyl, 2-(4-biphenylmethoxy)phenyl,2-(3-biphenylmethoxy)phenyl, benzyl,3-(6-(2,3-dihydro-1,1-dioxobenzo[b]thiophene)phenyl,2-(phenylsulfonyl)phenyl, 2,4-bis(methylsulfonyl)phenyl, and2-chloro-4-methylsulfonylphenyl. Additional useful values include8-quinolinyl, 5-methyl-8-quinolinyl, 4-benzo-2,1,3-thiadiazolyl,5-chloro-2-thiophenyl, 5-chloro-1,3-dimethyl-4-pyrazolyl, pyridyl,isoquinolinyl, and tetrahydroquinolinyl.

Useful values of R¹, when R¹ is phenyl substituted by R¹³R¹⁴NSO₂—include 2-(N-methylphenethylaminosulfonyl)phenyl,bis(2-methoxyethyl)aminosulfonylphenyl,2-N-methyl-(3,4-dimethoxyphenyl)ethylaminosulfonylphenyl,N-methyl-N-ethoxycarbonylmethyl)aminosulfonylphenyl,2-(N-methyl-N-(2-(2-pyridyl)ethyl)aminosulfonyl)phenyl,2-(N-propyl-N-(2-(2-pyridyl)ethyl)aminosulfonyl)phenyl,2-(N-ethyl-N-(4-pyridylmethyl)aminosulfonyl)phenyl,2-(N-methyl-N-(4-methoxyphenyl)aminosulfonyl)phenyl,2-(N-methyl-N-(4-methoxycarbonylphenyl)aminosulfonyl)phenyl,2-(N-(2-cyanoethyl)-N-(3-pyridylmethyl)aminosulfonyl)phenyl,2-(N,N-bis-(2-cyanoethyl)aminosulfonyl)phenyl,2-(N-(2-ethoxycarbonylethyl)-N-benzylaminosulfonyl)phenyl,2-(N-methyl-N-(2-(4-pyridyl)ethyl)aminosulfonyl)phenyl,2-(N-(ethoxycarbonylmethyl)-N-(2-pyridylmethyl)aminosulfonyl)phenyl,2-(N,N-,bis(ethoxycarbonylmethyl)aminosulfonyl)phenyl,2-(N,N-bis(carboxymethyl)aminosulfonyl)phenyl,2-(N-methyl-N-(4-carboxyphenyl)aminosulfonyl)phenyl,2-(N-(2-carboxyethyl)-N-benzylaminosulfonyl)phenyl,2-(N-(2-cyanoethyl)-N-(2-furanylmethyl)aminosulfonyl)phenyl,2-(N-ethyl-N-(1-benzyl-3-pyrrolidinyl)aminosulfonyl)phenyl,2-(N-benzyl-N-(2-(N,N-dimethylamino)ethyl)aminosulfonyl)phenyl,2-(N-methyl-N-(1-methyl-4-piperidinyl)aminosulfonyl)phenyl,2-(N-methyl-N-(3-pyridylmethyl)aminosulfonyl)phenyl,2-(N-ethyl-N-(2-(N,N-dimethylamino)ethyl)aminosulfonyl)phenyl,2-(2-(4-morpholinyl)ethylaminosulfonyl)phenyl,2-(N-methyl-N-(2-(N,N-dimethylamino)ethyl)aminosulfonyl)phenyl,N-ethyl-3,4-(methylenedioxy)anilinosulfonylphenyl,2-(N-methyl-N-(3-(N,N-dimethylamino)propyl)aminosulfonyl)phenyl, and2-(4-pyridylmethyl-aminosulfonyl)phenyl.

Further useful values of R¹, when R¹ is phenyl substituted byR¹³R¹⁴NSO₂— include 2-morpholinylsulfonylphenyl,2-(acetylpiperazinylsulfonyl)phenyl,2-(4-ethyloxycarbonyl)piperidinylsulfonyl,2-(4-carboxyl)piperidinylsulfonylphenyl,3-ethoxycarbonyl-1-piperidinosulfonyl)phenyl,3-carboxypiperidinosulfonyl)phenyl,2-methoxycarbonyl-1-pyrrolidionsulfonyl)phenyl,2-carboxy-1-pyrrolidionsulfonyl)phenyl,-2-(4-methylsulfonylpiperazin-1-ylsulfonyl)phenyl,2-(4-(2-pyrimidinyl)piperazin-1-ylsulfonyl)phenyl,2-(4-ethylpiperazin-1-ylsulfonyl)phenyl,2-(4-(piperidin-1-yl)piperidin-1-ylsulfonyl)phenyl,2-(4-(ethoxycarbonylmethyl)piperazin-1-ylsulfonyl)phenyl,2-(4-(carboxymethyl)piperazin-1-ylsulfonyl)phenyl,2-(4-(2-pyridyl)piperazinyl-sulfonyl)phenyl,2-(4-phenylpiperazinylsulfonyl)phenyl,2-(4-benzylpiperazinylsulfonyl)phenyl,2-(4-(2-methoxyphenyl)piperazinylsulfonyl)phenyl,2-(4-methylpiperazinylsulfonyl)phenyl,-2-(4-(pyrrolidin-1-yl)piperidin-1-ylsulfonyl)phenyl, and2-(4-ethoxycarbonyl-1-piperazinylsulfonyl)phenyl.

The groups R², R³ and R⁴ in Formula I substitute for any remaininghydrogen atoms on the benzene ring after allowing for attachment of themoiety —Z—R¹. Preferred compound are those where R², R³ and R⁴ areindependently hydrogen, C₁₋₄ alkyl, C₄₋₇ cycloalkyl, C₆₋₁₄ aryl,especially C₆₋₁₀ aryl, C₆₋₁₀ ar(C₁₋₄)alkyl, trifluoromethyl, halogen,hydroxyalkyl, cyano, nitro, carboxamide, carboxy, alkoxycarbonyl,carboxymethyl alkoxycarbonylmethyl, or cycloalkyloxycarbonyl.

Alternatively, R² and R³, when attached to adjacent carbon atoms on thebenzene ring, are one of —CH═CH—CH═CH— or —(CH₂)_(q)—, where q is from 2to 6, thereby forming a fused ring. Preferred values of R² together withR³ include —CH═CH—CH═CH—, —CH₂—CH₂—CH₂— and —CH₂—CH₂—CH₂—CH₂—. When R²and R³ together form a fused ring, R⁴ is preferably hdrogen.

Useful values of R², R³ and R⁴ include hydrogen, methyl, ethyl, chloro,bromo, trifluoromethyl, hydroxymethyl, methoxy, ethoxy, carboxamide,nitro, phenyl, cyclopropyl, hydroxy, isopropyl, methoxycarbonyl,ethoxycarbonyl and benzyl. Useful values of R², R³ and R⁴ also includeR² and R³ together forming —CH═CH—CH═CH— or —CH₂—CH₂—CH₂— and R⁴ beinghydrogen.

Preferred compounds are those of Formula I, where R⁶ is hydrogen or C₁₋₆alkyl.

Preferred compounds are those of Formula I, where R⁷, R⁸, R¹¹ and R¹²are independently one of hydrogen, C₁₋₆ alkyl, C₆₋₁₀ ar(C₁₋₆)alkyl,C₆₋₁₀ aryl, C₂₋₁₀ hydroxyalkyl or C₂₋₇ carboxyalkyl. Useful values ofR⁷, R⁸, R¹¹ and R¹² include hydrogen, methyl, ethyl, propyl, n-butyl,benzyl, phenylethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl,2-carboxymethyl, 3-carboxyethyl and 4-carboxypropyl. Additionalpreferred compounds are those wherein R⁷ and R⁸ are taken together toform —CH₂)_(y)— where y is most preferably 2. Another group of preferredcompounds are those where R⁸ and R¹¹ are taken together to form—(CH₂)_(r)— where r is most preferably 2.

Preferred compounds are those of Formula I, wherein R⁹ is hydrogen orC₁₋₆ alkyl, optionally substituted by one, two or three, preferably one,of amino, monoalkylamino, dialkylamino, alkoxy,hydroxy, alkoxycarbonyl,aryloxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, carboalkoxy, phenyl,cyano, trifluoromethyl, acetylamino, pyridyl, thiophenyl, furyl,pyrrolyl or imidazolyl.

Suitable values of R⁹ include hydrogen, methyl, ethyl, propyl, n-butyl,benzyl, phenethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl,carboxymethyl and carboxyethyl.

Preferred values of R¹⁰ in Formula I include hydrogen, C₁₋₆ alkyl, C₆₋₁₀ar(C₁₋₆)alkyl, C₆₋₁₀ aryl, C₂₋₁₀ hydroxyalkyl C₂₋₁₀ aminoalkyl, C₂₋₇carboxyalkyl, mono(C₁₋₄ alkyl)amino(C₁₋₈)alkyl, and di(C₁₋₄ alkyl)amino(C₁₋₈)alkyl. Suitable values of R¹⁰ include methyl, ethyl, propyl,n-butyl, benzyl, phenylethyl, 2-hydroxyethyl, 3-hydroxypropyl,4-hydroxybutyl, 2-aminoethyl, 2-carboxymethyl, 3-carboxyethyl,4-carboxypropyl and 2-(dimethylamino)ethyl.

Preferred values of R^(a), R^(b) and R^(c) in Formula I are hydrogen,hydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy, cyano or —CO₂R^(w), where R^(w), ineach instance, is preferably one of C₁₋₄alkyl, C₄₋₇cycloalkyl orbenzyloxycarbonyl. Suitable values of R^(a), R^(b) and R^(c) includehydrogen, methyl, ethyl, propyl, n-butyl, hydroxy, methoxy, ethoxy,cyano, —CO₂CH₃, —CO₂CH₂CH₃ and —CO₂CH₂CH₂CH₃. In the most preferredembodiments, R^(a), R^(b) and R^(c) are each hydrogen.

Also preferred at R^(a), R^(b) and R^(c) is the group —CO₂R^(w), whereR^(w) is one of

where R^(d)-R^(h) are defined as above. When R^(a), R^(b) and R^(c) are—CO₂R^(w), where R^(w) is one of one of the moieties, the resultingcompounds are prodrugs that possess desirable formulation andbioavailability characteristics. A preferred value for each of R^(d),R^(e) and R^(g) is hydrogen, R^(f) is methyl, and preferred values forR^(h) include benzyl and tert-butyl.

Preferred values of n in Formula I include from zero to 6, morepreferably from zero to 4, and most preferably zero, 1 or 2. Preferredvalues of m include from zero to 4, more preferably zero, 1, 2 or 3.

Compounds having the following formulae (Formula IIA and Formula IIB)have been discovered to have exceptional potency as inhibitors of serineproteases:

or a solvate, hydrate, pharmaceutically acceptable salt or prodrugthereof, wherein:

R²¹ is one of phenyl, naphthyl, thiophenyl, quinolinyl or isoquinolinyl,optionally substituted by one or two substituents independently selectedfrom the group consisting of halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, methoxy,trifluoromethyl, cyano, nitro, amino or dimethylamino; and when R²¹ isphenyl, said phenyl can be optionally ortho- substituted by C₁₋₆alkylsulfonyl, C₆₋₁₀ arylsulfonyl, C_(6-10 ar(C) ₁₋₆)alkylsulfonyl,C₆₋₁₀ arylsulfonamido, C₆₋₁₀ ar(C₁₋₆)alkylsulfonamido,N-morpholinosulfonyl, or R²²R²³NSO₂—, where R²² and R²³ areindependently selected from the group consisting of hydrogen, C₁₋₆alkyl, C₃₋₇ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₆₋₁₀ar(C₁₋₄)alkyl, pyridyl, pyridyl(C₁₋₄)alkyl, carboxy(C₁₋₆)alkyl, C₁₋₄alkoxycarbonyl(C₁₋₄)alkyl, cyano(C₂₋₆)alkyl, hydroxy(C₂₋₆)alkyl, C₁₋₄alkoxy(C₂₋₆)alkyl, mono- and di-(C₁₋₄)alkylamino(C₂₋₆)alkyl, or R²² andR²³ can be taken together with the nitrogen atom to which they areattached to form a heterocyclic ring selected from the group consistingof N-morpholinosulfonyl, N-piperazinylsulfonyl (optionally N′substituted with C₁₋₆ alkyl, C₁₋₆ hydroxyalkyl, C₆₋₁₀ aryl, C₆₋₁₀aryl(C₁₋₆)alkyl, C₁₋₆ alkylsulfonyl, C₆₋₁₀ arylsulfonyl, C₁₋₆alkylcarbonyl, morpholino or C₆₋₁₀ arylcarbonyl), N-pyrrolylsulfonyl,N-piperidinylsulfonyl, N-pyrrolidinylsulfonyl, N-dihydropyridylsulfonyl,N-indolylsufonyl, wherein said heterocyclic ring can be optionallysubstituted with one or two of hydroxy, C₁₋₈ alkanoyloxy, C₁₋₆ alkoxy,C₆₋₁₀ aryloxy, amino, mono- and di- C₁₋₆ alkylamino, C₁₋₈ alkanoylamino,C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₆₋₁₀ aryl, C₆₋₁₀ ar(C₁₋₄)alkyl,heterocycle, hetercycloalkyl, carboxy(C₁₋₆)alkyl, C₁₋₄alkoxycarbonyl(C₁₋₄)alkyl, cyano(C₂₋₆)alkyl, hydroxy(C₂₋₆)alkyl, C₁₋₄alkoxy(C₂₋₆)alkyl, mono- and di-(C₁₋₄)alkylamino(C₂₋₆)alkyl, carboxy,C₁₋₆ alkoxycarbonyl, carboxamido, formyl, C₁₋₆ alkanoyl, C₆₋₁₀ aroyl,C₆₋₁₀ ar(C₁₋₄)alkanoyl, sulfonyl, C₁₋₆ alkylsulfonyl, C₁₋₆alkoxysulfonyl, sulfonamido, phosphonyl, phosphoramido, or phosphinyl;

R²⁴ is hydrogen or C₁₋₄ alkyl;

Y′ is one of O, NR¹⁰, where R¹⁰ is defined as above, or a covalent bond;

a and b are 0, 1 or 2, preferably 1;

X′ is 0 or NR²⁹; and

R²⁹ is hydrogen or C₁₋₄ alkyl.

Preferred and suitable values of R²¹ are the same as those describedabove for R¹; Y′ is preferably O; a is preferably one; and X′ ispreferably O or NH.

Specific compounds within the scope of the invention include thefollowing:

3-[3-(2-chlorophenylsulfonyloxy)-5-methylphenoxy]propoxyguanidine;

3-[3-(2-methoxyphenylsulfonyloxy)-5-methylphenoxy]propoxyguanidine;

3-[5-methyl-3-(quinolinyl-8-sulfonyloxy)phenoxy]propoxyguanidinehydrochloride;

3-[3-(5-chloro-2-methoxyphenylsulfonyloxy)-5-methylphenoxy]propoxyguanidinehydrochloride;

3-[3-(5-chlorothiophenyl-2-sulfonyloxy)-5-methylphenoxy]propoxyguanidinehydrochloride;

3-[3-(2-cyanophenylsulfonyloxy)-5-methylphenoxy]propoxyguanidinehydrochloride;

3-[3-(5-isoquinolinylsulfonyloxy)-5-methylphenoxy]propoxyguanidinehydrochloride;

3-[5-methyl-3-[2-(methylsulfonyl)phenylsulfonyloxy]phenoxy]propoxyguanidinehydrochloride

3-[5-methyl-3-(1,2,3,4-tetrahydroquinolinyl-8-sulfonyloxy)phenoxy]propoxyguanidineacetate;

3-[5-hydroxymethyl-3-(quinolinyl-8-sulfonyloxy)phenoxy]propoxyguanidineaceticacid salt;

1-[[5-methyl-3-(2-methylsulfonylphenylsulfonyloxy)phenoxy]methyl]cyclopropylmethoxyguanidine hydrochloride;

1-[[5-methyl-3-(2-cyanophenylsulfonyloxy)phenoxy]methyl]cyclopropylmethoxyguanidineacetate;

1-[[5-methyl-3-(quinolinyl-8-sulfonyloxy)phenoxy]methyl]cyclopropylmethoxyguanidineacetate;

3-[5-methyl-3-(2-morpholinylsulfonylphenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride;

3-[5-methyl-3-(2-(acetylpiperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride;

3-[5-methyl-3-(2-(N-methylphenethylaminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine hydrochloride;

3-[5-methoxy-3-(2-methylsulfonylphenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride;

3-[5-ethyl-3-(2-methylsulfonylphenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride;

3-[5-methyl-3-(2-(phenylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride;

3-[5-methyl-3-(2-(4-ethyloxycarbonyl)piperidinylsulfonylphenylsulfonyloxy)phenoxy]propoxyguanidine hydrochloride;

2-[5-methyl-3-(2-(methylsulfonyl)phenylsulfonyloxy)phenoxy]ethoxyguanidine;

2-hydroxy-3-[5-methyl-3-(2-methylsulfonyl)phenylsulfonyloxyphenoxy]propoxyguanidine;

3-[3-(2,4-bis(methylsulfonyl)phenylsulfonyloxy)-5-methylphenoxy]propoxyguanidinehydrochloride;

3-[5-methyl-3-(3-methylsulfonyl)phenylsulfonyloxyphenoxy]propoxyguanidinehydrochloride;

3-[3-((2-chloro-4-methylsulfonyl)phenylsulfonyloxy)-5-methylphenoxy]propoxyguanidinehydrochloride;

3-(6-(2,3-dihydro-1,1-dioxobenzo[b]thiophene)phenylsulfonyloxy)-5-methylphenoxypropoxy]guanidinetrifluoroacetate;

3-[5-methyl-3-(2-(4-carboxyl)piperidinylsulfonylphenylsulfonyloxy)phenoxy]propoxyguanidine;

3-[5-methyl-3-(3-methylquinolinyl-8-sulfonyloxy)phenoxy]propoxyguanidinediacetate;

3-[5-methyl-3-[2-(N-hydroxy)aminophenylsulfonyloxy]phenoxy]propoxyguanidinehydrochloride;

3-[5-methyl-3-[2-aminophenylsulfonyloxy]phenoxy]propoxyguanidinehydrochloride;

3-[3-(2-(4-biphenylmethoxy)phenylsulfonyloxy)-5-methylphenoxy]propoxyguanidine;

3-[3-(2-(3-biphenylmethoxy)phenylsulfonyloxy)-5-methylphenoxy]propoxyguanidinehydrochloride;

1-[(3-benzyloxy-5-methylphenoxy)methyl]-1,1-cyclopropylethoxyguanidine;

3-[5-methyl-3-bis(2-methoxyethyl)aminosulfonylphenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride;

3-[5-methyl-3-(N-ethyl-3,4-(methylenedioxy)anilinosulfonylphenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride;

3-[5-methyl-3-(2-N-methyl-(3,4-dimethoxyphenyl)ethylaminosulfonylphenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride;

3-[5-methyl-3-((3-ethoxycarbonyl-1-piperidinosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride

3-[5-methyl-3-((3-carboxypiperidinosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride;

3-[5-methyl-3-((2-methoxycarbonyl1-pyrrolidinosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride;

3-[5-methyl-3-((2-carboxy-1-pyrrolidinosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride;

3-[5-methyl-3-(N-methyl-N-ethoxyarbonylmethyl)aminosulfonylphenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride;

3-[5-methyl-3-(N-methyl-N-ethoxyarbonylmethyl)aminosulfonylphenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride;

3-[5-methyl-3-(2-(4-methylsulfonylpiperazin-1-ylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride;

3-[5-methyl-3-(2-(4-(2-pyrimidinyl)piperazin-1-ylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride;

3-[5-methyl-3-(2-(N-methyl-N-(2-(2-pyridyl)ethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride;

3-[5-methyl-3-(2-(N-propyl-N-(2-(2-pyridyl)ethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinedihydrochloride;

3-[5-methyl-3-(2-(N-ethyl-N-(4-pyridylmethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinedihydrochloride;

3-[5-methyl-3-(2-(N-methyl-N-(4-methoxyphenyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride;

3-[5-methyl-3-(2-(4-ethylpiperazin-1-ylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinedihydrochloride;

3-[5-methyl-3-(2-(N-methyl-N-(4-methoxycarbonylphenyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride;

3-[5-methyl-3-(2-(N-(2-cyanoethyl)-N-(3-pyridylmethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinedihydrochloride;

3-[5-methyl-3-(2-(N,N-bis-(2-cyanoethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride;

3-[5-methyl-3-(2-(N-(2-ethoxycarbonylethyl)-N-benzylaminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride;

3-[5-methyl-3-(2-(4-(piperidin-1-yl)piperidin-1-ylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride;

3-[5-methyl-3-(2-(N-methyl-N-(2-(4-pyridyl)ethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride;

3-[5-methyl-3-(2-(N-(ethoxycarbonylmethyl)-N-(2-pyridylmethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride;

3-[5-methyl-3-(2-(N,N-bis(ethoxycarbonylmethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride;

3-[5-methyl-3-(2-(4-(ethoxycarbonylmethyl)piperazin-1-ylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinedihydrochloride;

3-[5-methyl-3-(2-(N,N-bis(carboxymethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine;

3-[5-methyl-3-(2-(N-methyl-N-(4-carboxyphenyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine;

3-[5-methyl-3-(2-(N-(2-carboxyethyl)-N-benzylaminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine;

3-[5-methyl-3-(2-(4-(carboxymethyl)piperazin-1-ylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine;

3-[5-methyl-3-(2-(4-(2-pyridyl)piperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride;

3-[5-methyl-3-(2-(4-phenylpiperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride;

3-[5-methyl-3-(2-(4-benzylpiperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride;

3-[5-methyl-3-(2-(4-(2-methoxyphenyl)piperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride;

3-[5-methyl-3-(2-(N-(2-cyanoethyl)-N-(2-furanylmethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine;

3-[5-methyl-3-(2-(4-methylpiperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride;

3-[5-methyl-3-(2-(N-ethyl-N-(1-benzyl-3-pyrrolidinyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinedihydrochloride;

3-[5-methyl-3-(2-(N-benzyl-N-(2-(N,N-dimethylamino)ethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinedihydrochloride;

3-[5-methyl-3-(2-(N-methyl-N-(1-methyl-4-piperidinyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinedihydrochloride;

3-[5-methyl-3-(2-(N-methyl-N-(3-pyridylmethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinedihydrochloride;

3-[5-methyl-3-(2-(N-ethyl-N-(2-(N,N-dimethylamino)ethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinedihydrochloride;

3-[5-methyl-3-(2-(2-(4-morpholinyl)ethylaminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinedihydrochloride;

3-[5-methyl-3-(2-(N-methyl-N-(2-(N,N-dimethylamino)ethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine dihydrochloride;

3-[5-methyl-3-(2-(4-(pyrrolidin-1-yl)piperidin-1-ylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine;

3-[5-methyl-3-(2-(4-ethoxycarbonyl-1-piperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride;

3-[5-methyl-3-(2-(N-methyl-N-(3-(N,N-dimethylamino)propyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine;

3-[5-methyl-3-(2-(4-pyridylmethylaminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine;

N-methyl-N-{3-[5-methyl-3-(2-(methylsulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidinehydrochloride;

3-[3-methyl-5-(N-methyl-2-(methylsulfonyl)phenylsulfonylamino)phenoxy]propoxyguanidinehydrochloride;

3-[3-(2-chlorophenylsulfonyloxy)-5-methylphenoxy]-propylaminoguanidinediacetate;

[3-[5-methyl-3-(2-trifluoromethylphenylsulfonyloxy)phenoxy]-propylamino]guanidinehydrochloride;

[3-[3-(5-chlorothiophenyl-2-sulfonyloxy)-5-methylphenoxypropylaminoguanidineacetate;

[3-[3-(2-methoxyphenylsulfonyloxy)-5-methylphenoxy]-propylamino]guanidinediacetate;

[3-[3-(2-cyanophenylsulfonyloxy)-5-methylphenoxy]propylamino]guanidineacetate;

as well as pharmaceutically acceptable salts thereof, for example thehydrochloride and acetate salts thereof. Structures for these compoundsare provided in the pages prior to the claims.

Alternative embodiments of the present invention include compounds ofFormula I in which two “R” groups together form a saturated orunsaturated hydrocarbon bridge, thus forming an additional cyclic moietyin the resulting compounds. Alternative embodiments include compounds ofFormula I wherein Z, R¹-R⁴, Y, m and n are as defined above; and:

A. R⁷ and R¹² are taken together to form —(CH₂)_(o)—, where o is 1, 2 or3; R¹¹ is hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl or carboxyalkyl;R⁸ is hydrogen and R⁶, R^(a), R^(b) and R^(c) are defined as above; or

B. R¹¹ is hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl or carboxyalkyl;R⁷ is hydrogen;

R⁸ and R¹² are taken together to form —(CH₂)—(CH₂)—(CH₂)_(p)—, where pis 1,2 or 3; and R⁶, R^(a), R^(b) and R^(c) are defined as above; or

C. R⁶ and R^(b) are taken together to form —(CH₂)—(CH₂)_(r)— or═CH—N═CH—NH—, where r is 1, 2 or 3; R^(a) is hydrogen or hydroxy; R^(c)is hydrogen, alkyl, hydroxy, alkoxy, aryloxy, aralkoxy,alkoxycarbamoyloxy, cyano or —CO₂R^(w)—, where R^(w) is as definedabove; R⁷, R⁸, R¹¹ and R¹² are each independently one of hydrogen,alkyl, aralkyl, aryl, hydroxyalkyl or carboxyalkyl, or R⁷ and R⁸ aretaken together to form —(CH₂)_(y)—, where y is zero, 1 or 2; or

D. R^(a) and R^(c) are taken together to form —CH₂—(CH₂)_(s)—, where sis 1 or 2; R⁶ is hydrogen, alkyl, alkoxy, aryloxy, aralkoxy,alkoxycarbonyloxy, cyano or —CO₂R^(w)—, where R^(w) is as defined above;and R⁷, R⁸, R¹¹ and R¹² are each independently one of hydrogen, alkyl,aralkyl, aryl, hydroxyalkyl or carboxyalkyl, or R⁷ and R⁸ are takentogether to form —(CH₂)_(y)—, where y is zero, 1 or 2.

Thus, compounds having formulae III, IV, V and VI are contemplated:

wherein R¹-R⁴, Z, Y, R⁶-R¹², R^(a)-R^(c), n, m, o, p, r and s aredefined as above. Preferred values for each of these variables are thesame as described above for Formula I. Specific compounds within thescope of these formulae include:

It is also to be understood that the present invention is considered toinclude stereoisomers as well as optical isomers, e.g. mixtures ofenantiomers as well as individual enantiomers and diastereomers, whicharise as a consequence of structural asymmetry in selected compounds ofthe present series.

The compounds of Formula I may also be solvated, especially hydrated.Hydration may occur during manufacturing of the compounds orcompositions comprising the compounds, or the hydration may occur overtime due to the hygroscopic nature of the compounds.

Certain compounds within the scope of Formula I are derivatives referredto as prodrugs. The expression “prodrug” denotes a derivative of a knowndirect acting drug, which derivative has enhanced deliverycharacteristics and therapeutic value as compared to the drug, and istransformed into the active drug by an enzymatic or chemical process;see Notari, R. E., “Theory and Practice of Prodrug Kinetics,” Methods inEnzymology, 112:309-323 (1985); Bodor, N., “Novel Approaches in ProdrugDesign,” Drugs of the Future, 6(3):165-182 (1981); and Bundgaard, H.,“Design of Prodrugs: Bioreversible-Derivatives for Various FunctionalGroups and Chemical Entities,” in Design of Prodrugs (H. Bundgaard,ed.), Elsevier, N.Y. (1985). Useful prodrugs are those where R^(a),R^(b) and/or R^(c) are —CO₂R^(w), where R^(w) is defined above. See,U.S. Pat. No. 5,466,811 and Saulnier et al., Bioorg. Med. Chem. Lett.4:1985-1990 (1994).

The term “alkyl” as employed herein by itself or as part of anothergroup refers to both straight and branched chain radicals of up to 12carbons, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl,isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl.

The term “alkenyl” is used herein to mean a straight or branched chainradical of 2-20 carbon atoms, unless the chain length is limitedthereto, including, but not limited to, ethenyl, 1-propenyl, 2-propenyl,2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. Preferably, thealkenyl chain is 2 to 10 carbon atoms in length, more preferably, 2 to 8carbon atoms in length most preferably from 2 to 4 carbon atoms inlength.

The term “alkynyl” is used herein to mean a straight or branched chainradical of 2-20 carbon atoms, unless the chain length is limitedthereto, wherein there is at least one triple bond between two of thecarbon atoms in the chain, including, but not limited to, acetylene,1-propylene, 2-propylene, and the like. Preferably, the alkynyl chain is2 to 10 carbon atoms in length, more preferably, 2 to 8 carbon atoms inlength, most preferably from 2 to 4 carbon atoms in length.

In all instances herein where there is an alkenyl or alkynyl moiety as asubstituent group, the unsaturated linkage, i.e., the vinylene oracetylene linkage is preferably not directly attached to a nitrogen,oxygen or sulfur moiety.

The term “alkoxy” is used herein to mean a straight or branched chainradical of 1 to 20 carbon atoms, unless the chain length is limitedthereto, bonded to an oxygen atom, including, but not limited to,methoxy, ethoxy, n-propoxy, isopropoxy, and the like. Preferably thealkoxy chain is 1 to 10 carbon atoms in length, more preferably 1 to 8carbon atoms in length.

The term “aryl” as employed herein by itself or as part of another grouprefers to monocyclic or bicyclic aromatic groups containing from 6 to 12carbons in the ring portion, preferably 6-10 carbons in the ringportion, such as phenyl, naphthyl or tetrahydronaphthyl.

The term “heteroaryl” as employed herein refers to groups having 5 to 14ring atoms; 6, 10 or 14 π electrons shared in a cyclic array; andcontaining carbon atoms and 1, 2 or 3 oxygen, nitrogen or sulfurheteroatoms (where examples of heteroaryl groups are: thienyl,benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, pyranyl,isobenzofuranyl, benzoxazolyl, chromenyl, xanthenyl, phenoxathiinyl,2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl,indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl,phthalazinyl, naphthyridinyl, quinazolinyl, cinnolinyl, pteridinyl,4αH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl,perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl,isoxazolyl, furazanyl and phenoxazinyl groups).

The term “aralkyl” or “arylalkyl” as employed herein by itself or aspart of another group refers to C₁₋₆ alkyl groups as discussed abovehaving an aryl substituent, such as benzyl, phenylethyl or2-naphthylmethyl.

The term “cycloalkyl” as employed herein by itself or as part of anothergroup refers to cycloalkyl groups containing 3 to 9 carbon atoms.Typical examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl and cyclononyl.

The terms “alkoxy” refers to any of the above alkyl groups linked to anoxygen atom.

The term “halogen” or “halo” as employed herein by itself or as part ofanother group refers to chlorine, bromine, fluorine or iodine withchlorine being preferred.

The term “monoalkylamine” as employed herein by itself or as part ofanother group refers to an amino group which is substituted with onealkyl group having from 1 to 6 carbon atoms.

The term “dialkylamine” as employed herein by itself or as part ofanother group refers to an amino group which is substituted with twoalkyl groups, each having from 1 to 6 carbon atoms.

The term “hydroxyalkyl” as employed herein refers to any of the abovealkyl groups substituted by one or more hydroxyl moieties.

The term “carboxyalkyl” as employed herein refers to any of the abovealkyl groups substituted by one or more carboxylic acid moieties.

The term “heterocyclic” is used herein to mean a saturated or wholly orpartially unsaturated 3-7 membered monocyclic, or 7-10 membered bicyclicring system, which consists of carbon atoms and from one to fourheteroatoms independently selected from the group consisting of O, N,and S, wherein the nitrogen and sulfur heteroatoms can be optionallyoxidized, the nitrogen can be optionally quaternized, and including anybicyclic group in which any of the above-defined heterocyclic rings isfused to a benzene ring, and wherein the heterocyclic ring can besubstituted on carbon or on a nitrogen atom if the resulting compound isstable. Especially useful are rings containing one oxygen or sulfur, oneto three nitrogen atoms, or one oxygen or sulfur combined with one ortwo nitrogen atoms. Examples of such heterocyclic groups includepiperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl,pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl,imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl,oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl,thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl,quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl,benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl,thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide,thiamorpholinyl sulfone, and oxadiazolyl. Morpholino is the same asmorpholinyl.

The term “heteroatom” is used herein to mean an oxygen atom (“O”), asulfur atom (“S”) or a nitrogen atom (“N”). It will be recognized thatwhen the heteroatom is nitrogen, it may form an NR^(y)R^(z) moiety,wherein R^(y) and R^(z) are, independently from one another, hydrogen orC₁ to C₈ alkyl, or together with the nitrogen to which they are bound,form a saturated or unsaturated 5-, 6-, or 7-membered ring.

Another aspect of the present invention is a process for preparing anaminoguanidine compound of Formula I, comprising reacting anaminoguanidine of the formula

wherein R⁶, R^(a), R^(b) and R^(c) are defined as above, with acarbonyl-containing compound of the formula

wherein R¹-R⁴, Z, Y, n, m, R⁷, R⁸, R¹¹ and R¹² are defined as above toform an amidinohydrazone, and thereafter selectively reducing thehydrazone carbon to nitrogen double bond of the amidinohydrazone.

The aminoguanidine is typically provided as a salt, preferably thenitrate salt. The first step proceeds at ambient temperature usingalcohol as a solvent. An acid, such as 4N HCl in dioxane is added to thereaction mixture. The reaction is more fully described herein.

Another aspect of the present invention is a process for preparing ahydroxyguanidine compound of Formula I, comprising reacting analkoxyamine compound of the formula

wherein R¹-R⁴, Z, Y, n, m, R⁷, R⁸, R¹¹ and R¹² are defined as above witha guanidinylating reagent. Preferred guanidinylating reagents include:aminoiminosulfonic acid, optionally substituted1H-pyrazole-1-carboxamidines, or N,N′-bis(tert-butoxycarbonyl) S-methylisothiourea.

The invention is also directed to alkoxyamine intermediates that areuseful for forming the protease inhibiting compounds of Formula I. Theseintermediates are represented by Formula IX:

wherein R¹-R⁴, Z, Y, n, m, R⁷, R⁸, R¹¹ and R¹² are defined as above forFormula I.

Schemes Ia, Ib, and Ic outline the synthetic steps to produce compoundsof the present invention where R¹—Z is R¹—C(R^(y)R^(z))₂O— or R¹—SO₂O—.Scheme Ia illustrates but is not limited to the preparation of thecompounds of Examples 1-8, 10-18, 21-22, 28-33, and 82-86.

Phenols 1 (where P^(a)=H) are converted to monosulfonates 2 by treatmentwith appropriate sulfonyl chlorides. Preferred conditions includetreating phenol 1 with a sulfonyl chloride in a biphasic system composedof an organic solvent, such as an ether, and an aqueous phase saturatedwith NaHCO₃. Alternatively, the reaction may be effected first bydeprotonating 1 with one equivalent of a strong base, most preferablyNaH, in a polar organic solvent, such as N,N-dimethylformamide ortetrahydrofuran, followed by treating the deprotonated phenol with thesulfonyl chloride. Still alternatively, phenol 1, in a typical organicsolvent, such as dichloromethane, may be converted to 2 by treating thephenol with sulfonyl chloride in the presence of an amine base, such as4-methylmorpholine.

Phenols 1 may be monoprotected (P^(a) is a protecting group) with avariety of protecting groups known in the art, such as esters and benzylethers (Greene, T. W. and Wuts, P. G. M., Protective Groups in OrganicSynthesis, 2nd edition, John Wiley and Sons, Inc. New York (1991)).Deprotection of the hydroxy groups is routinely accomplished using thereaction conditions well known in the art. For example, deprotection ofbenzyl ethers may be effected through catalytic hydrogenation usingpalladium on carbon as a catalyst in solvents such as ethanol ortetrahydrofuran. Deprotection of an acetate is accomplished by basichydrolysis, most preferably with sodium hydroxide in aqueoustetrahydrofuran.

Phenols 2 are coupled to 3 (for L=OH) using a Mitsunobu couplingprocedure (Mitsunobu, O., Synthesis 1 (1981)), where P^(b) of 3 may be asuitable alcohol protecting group. Alternatively, suitable diols(P^(b)=H) may be used in the Mitsunobu reaction. Preferred couplingconditions include using a trialkylphosphine or triarylphosphine, suchas triphenylphosphine or tri-n-butylphosphine, in a suitable solvent,such as tetrahydrofuran or dichloromethane, and an azodicarbonylreagent, such as diethyl azodicarboxylate or1,1′-(azodicarbonyl)dipiperidine. Typical P^(b) (where P^(b) is analcohol protecting group) is well known in the art, such as esters andbenzyl ethers (Greene, T. W. and Wuts, P. G. M., supra). Alternatively,where L is a reactive leaving group such as halide or sulfonate, phenol2 may be treated with a base, such as sodium hydride, in a solvent, suchas N,N-dimethylformamide, and then treated with 3. Removal of P^(b) isroutinely accomplished using the reaction conditions well known in theart. For example, deprotection of benzyl ethers may be effected throughcatalytic hydrogenation using palladium on carbon as a catalyst insolvents such as ethanol or tetrahydrofuran. Deprotection of an acetateis accomplished by basic hydrolysis, most preferably with sodiumhydroxide in aqueous tetrahydrofuran.

Alternatively still, alcohol 4 can be obtained by reduction of theappropriate aldehyde or ketone 7 (obtained from 2 as described below)with a suitable reducing agent, such as sodium or lithium borohydride(Wallbridge, J. Prog. Inorg. Chem 11:99-231 (1970)).

Alcohol 4 is converted to 9 employing a Mitsunobu reaction with anN-hydroxycyclic imide derivative such as N-hydroxyphthalimide. Unveilingof the phthalimide protecting group is accomplished using standardconditions well known in the art (Greene, T. W. and Wuts, P. G. M.,supra), for example, sodium borohydride in a mixture of an appropriatealcohol (e.g. ethanol or 2-propanol)/water followed by acidification.Alternatively, removal of the protecting group may be accomplished usinghydrazine or methylamine.

Guanidinylation of the resulting alkoxyamine to 10 is achieved usingstandard reagents such as aminoiminosulfonic acid (Miller, A. E. andBischoff, J. J. Synthesis 777 (1986)), or 1H-pyrazole-1-carboxamidinehydrochloride (Bernatowicz, M. S. et. al. J Org. Chem 57(8):2497(1992)), or with substituted guanidinylating reagents such asN,N′-bis(tert-butoxycarbonyl)-S-methylisothiourea (Bergeron, R. J. andMcManis, J. S. J Org Chem. 52:1700 (1987)) or N—R^(a), N—R^(b),N′—R^(c)-1H-pyrazole-1-carboxamidine, where R^(a), R^(b) and R^(c) aredefined as above for Formula I. Useful 1H-pyrazole-1-carboxamidinesinclude N,N′-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine andN,N′-bis(benzyloxycarbonyl)-1H-pyrazole-1-carboxamidine (all of whichcan be prepared according to Bernatowicz, M. S. et. al., TetrahedronLetters 34:3389 (1993)).

Conversion of alcohol 4 to the corresponding aldehyde or ketone 7 isaccomplished using routine procedures for the oxidation of alcohols (seefor example Carey, F. A, Sundberg, R. J. Advanced Organic Chemistry,Part B: Reactions and Synthesis, 3rd edition, Plenum Press, New York(1990)) such as the Swern oxidation (Mancuso, A. J. et al., Journal ofOrganic Chemistry 3329 (1976)) pyridinium chlorochromate (Corey, E. J.and Suggs, J. W. Tetrahedron Letters 2647 (1975)) pyridinium dichromate(Corey, E. J. and Schmidt, G. Tetrahedron Letters 399 (1979)), or sulfurtrioxide pyridine complex/dimethylsulfoxide (Tetrahedron Letters 28:1603(1987)).

Still alternatively, 2 may be coupled directly to 5 where L=OH or areactive leaving group such as halide, alkyl sulfonate, or arylsulfonate. In the case of L=OH, the Mitsunobu coupling procedure may beused. In cases where L is a reactive leaving group such as halide orsulfonate, phenol 2 may be treated with a base, such as sodium hydride,in a solvent, such as NAN-dimethylformamide, and then treated with 5.

Alternatively, phenol 2 may be converted to 7 by the Mitsunobu reactionusing 6 wherein L=OH and P^(c) is an aldehyde or ketone protecting groupwhich is well known in the art (Greene, T. W. and Wuts, P. G. M.,supra), for example, a dimethyl ketal or acetal, 1,3-dioxolane group, or1,3-dioxane group. Alternatively, where L of 6 is a reactive leavinggroup such as halide or sulfonate, phenol 2 may be treated with a base,such as sodium hydride in a solvent such as N,N-dimethylformamide, andthen treated with 6. P^(c) may then be removed to afford 7 usingstandard conditions well known in the art, for example,p-toluenesulfonic acid in acetone (Greene, T. W. and Wuts, P. G. M.,supra).

Compound 7 is then converted to amidinohydrazone 8 using standardconditions, for example, treatment with an aminoguanidine, such asaminoguanidine or 2-hydrazinoimidazoline, optionally in the presence ofan acid such as nitric acid, hydrogen chloride, or hydrogen bromide, inan appropriate solvent, for example, ethanol or methanol, which, inaddition, may contain other solvents such as dichloromethane ortetrahydrofuran. Conversion of 8 to 11 is accomplished under reducingconditions well known in the art, for example, lithium borohydride in anappropriate solvent such as tetrahydrofuran or methanol at varioustemperatures up to reflux. As an alternative method, catalytichydrogenation with palladium on carbon catalyst can be employed.

When R^(a), R^(b) and/or R^(c) are a protecting group, for examplet-butyloxycarbonyl (Boc), these protecting groups can be optionallyremoved by treatment with acid, usually trifluoroacetic acid in asuitable solvent such as dichloromethane or water, or by HCl gasdissolved in a suitable solvent, such as 1,4-dioxane.

A variation of Scheme Ia (Scheme Ib) involves the use of monoprotectedphenols in the synthesis of Examples 19-20, 23-26, and 80. Phenols 1 aremonoprotected (P^(a) is a protecting group) with a variety of protectinggroups known in the art such as esters and benzyl ethers (Greene, T. W.& Wuts, P. G. M., supra). Monoprotected phenols 1 are coupled to 3 asdescribed for Scheme Ia. Deprotection and another Mitsunobu couplingwith an N-hydroxy imide derivative, such as N-hydroxyphthalimide, asdescribed for Scheme Ia, gives the alkoxyphthalimides 16. The removal ofthe phthalimide group, as described for Scheme Ia, produces thealkoxyamine. The alkoxyamines are subsequently converted to theoptionally protected alkoxyguanidines, using the standardguanidinylation reagents, such as aminoiminosulfonic acid (Miller, A. E.& Bischoff, J. J., supra) or 1H-pyrazole-1-carboxamidine hydrochloride(Bernatowicz, M. S. et. al., supra), or with substituted guanidinylatingreagents such as N,N′-bis(tert-butoxycarbonyl)-S-methylisothiourea(Bergeron, R. J. & McManis, J. S., supra) or N—R^(a), N—R^(b),N′—R^(c)-1H-pyrazole-1-carboxamidine includingN,N′-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine andN,N′-bis(benzyloxycarbonyl)-1H-pyrazole-1-carboxamidine (all of whichcan be prepared according to (Bernatowicz, M. S. et. al., supra) whereR^(a), R^(b) and R^(c) are as defined above. The phenolic protectinggroup, P^(a), may be removed to give 17 and the resultant phenolic groupreacted with sulfonyl chlorides. Optionally, the protectedalkoxyguanidines may be alkylated on the unprotected nitrogen of theguanidine using a Mitsunobu coupling with an alcohol R⁶OH (e.g.,methanol gives the N-methyl alkoxyguanidine derivative). Finally, theguanidine protecting groups, R^(a), R^(b), and R^(c), may be removed asoutlined for Scheme Ia.

Scheme Ic outlines the synthesis of the 1,2-benzenedisulfo derivativesdescribed in Examples 34-79. In particular, Examples 34-68 weresynthesized by the reaction of 1,2-benzenedisulfonic anhydride 18(Koeberg-Telder et al., J Chem. Soc. Perkin II 98 (1973)) with secondaryamines, R¹³R¹⁴NH, in the presence of a base such as a tertiary aminewhere R¹³ and R¹⁴ are as defined above, provided that they are bothother than hydrogen. The resultant monosulfonic acid salt is convertedto the sulfonyl chloride in situ by reaction with 1 equivalent of oxalylchloride. The resultant sulfonyl chloride is reacted in situ with thephenol 17. The optional guanidine protecting groups, R^(a), R^(b), andR^(c), may be removed as outlined for Scheme Ia to give 19.

The Examples of 68-79 were alternatively synthesized by the reaction ofthe benzenedisulfonic anhydride 18 with the O-phthalimide 16 (P^(a)=H).The resultant monosulfonic acid salt is converted in situ to thesulfonyl chloride with 1 equivalent of oxalyl chloride. The resultantsulfonyl chloride is reacted with amines, especially primary anddiamines, to produce sulfonamides. The O-amine is next deprotected andguanidinylated by the means outlined for Scheme Ia. Finally, theoptional guanidine protecting groups, R^(a), R^(b), and R^(c), may beremoved as outlined for Scheme Ia to give 19.

Schemes IIa and IIb outline the syntheses of primary and secondarysulfonamidophenoxy derivatives and carboxamido derivatives, where R¹—Z—is R¹—SO₂NR¹⁰— or R¹—CONR¹⁰—.

Scheme IIa outlines the synthesis of intermediate 1,3-aminophenols whichare further converted to sulfonamidophenoxy derivatives where R¹—Z isR¹—SO₂NR¹⁰— and R¹⁰ is preferably an alkyl group, as exemplified byExample 81, or are alternatively converted to carboxamidophenoxyderivatives where R¹—Z is R¹—CONR¹⁰—. Phenols 1 are reacted with2-bromo-2-methyl propanamide in the presence of a base, such as sodiumhydride, to give the aryloxyamides 20. The aryloxyamides 20 are treatedwith sodium hydride in a high boiling solvent, such as1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, at an elevatedtemperature (e.g., 100° C. for 3 h) and undergo the Smiles rearrangementto the anilides 21 (Cotts & Southcott, J Chem. Soc. PTl 767 (1990)). Theanilides 21 are hydrolyzed using strong base and elevated temperature(e.g., 10N sodium hydroxide at reflux) for extended times (e.g., 2 days)in order to provide the corresponding anilines 22. The anilines 22 areconverted to sulfonamides 23 by the reaction with sulfonyl chlorides inthe presence of a suitable base, such as a tertiary amine. Thesulfonamides 23 are reacted with base (e.g., cesium carbonate) and R¹⁰Lwhere L is a reactive leaving group, such as halide or sulfonate.Alternatively, the anilines 22 are converted to carboxamides by thereaction with acyl chlorides (R¹COCl) in the presence of a suitable basesuch as a tertiary amine. Still alternatively, the carboxamides may beproduced by the reaction of anilines 22 with carboxylic acids (R¹COOH)by any of the known peptide coupling reagents, such as1,3-dicyclohexylcarbodiimide or Castro's reagent (BOP) (Castro B., etal., Tetrahedron Lett. 1219 (1975)). The phenolic protecting group,P^(a), is then removed and the resultant phenols 24 are coupled with 3as described for Scheme Ia. After removal of the alcohol protectinggroup, P^(b), the alcohol is coupled to N-hydroxy imides, such asN-hydroxyphthalimide, as described for Scheme Ia. The removal of thephthalimide group, as described for Scheme Ia, produces the alkoxyamine.The alkoxyamines are subsequently converted to the optionally protectedalkoxyguanidines, using the standard guanidinylation reagents outlinedfor Scheme Ia. Finally, the guanidine protecting groups, R^(a), R^(b),and R^(c), may be optionally removed as outlined for Scheme Ia toproduce the target 27.

An alternative method to synthesize sulfonamides, especially unalkylatedsulfonamides (where R¹⁰=H) is shown in Scheme IIb. Nitrophenol 28 iscoupled to 3 by standard techniques. Preferably, the reaction iseffected by the Mitsunobu reaction (where L is OH). Alternatively, thenitrophenol is treated with a base, such as NaH, in a suitable solventsuch as N,N-dimethylformamide or tetrahydrofuran, followed by theaddition of 3 (where L is a reactive group, such as Cl, Br, I orsulfonate). After P^(b) group removal, the alcohol 29 undergoes aMitsunobu coupling with an N-hydroxy imide, such asN-hydroxyphthalimide, as described in Scheme Ia. The nitro group of 30is thereafter reduced, for example, by catalytic reduction usingpalladium on carbon in a suitable solvent such as ethanol ortetrahydrofuran. The resulting product is treated with an appropriatesulfonyl chloride (R¹SO₂Cl) to provide the sulfonamide 31. At thispoint, the sulfonamide group may be optionally alkylated as described inScheme IIa. Alternatively, the resulting product from nitro reduction istreated with an appropriate acyl chloride (R¹COCl) to provide thecorresponding carboxamide 31. Still alternatively, the carboxamides 31may be produced by the reaction of the product from nitro reduction withcarboxylic acids (R¹COOH) by any of the known peptide coupling reagents,such as 1,3-dicyclohexylcarbodiimide or Castro's reagent (BOP). Removalof the O-amine protecting group and guanidinylation of the O-amine areaccomplished by methods described in Scheme Ia. Finally, the O-guanidineprotecting groups, R^(a), R^(b), and R^(c), may be removed as outlinedin Scheme Ia to give the target 32.

The compounds of the present invention where R¹—Z isR¹—CH(R^(y)R^(z))NR¹⁰— can be synthesized by the steps outlined inScheme IIc. Aniline 22 is converted to 33, where R^(x) is H, byreductive amination with a suitable carbonyl component, R¹COR^(y). Thepreferred reducing agent is tetramethylammonium triacetoxyborohydride.Alternatively, sodium triacetoxyborohydride or sodium cyanohydride maybe used. Still alternatively, reductive amination may be carried out byforming an imine (Schiff base) between the amine and the carbonylcomponent using a catalytic amount of acid such as p-toluenesulfonicacid, followed by reduction with sodium borohydride. Stillalternatively, the imine may be reduced using catalytic hydrogenationusing a catalyst such as palladium on carbon in standard solvent such asethanol. As an alternate to a reductive amination, aniline 22 may bereacted with R¹(R^(y)R^(x))L, where L is a reactive leaving group, suchas halide or sulfonate. The remaining conversion of 33 to 37, whichcomprises of pa removal, coupling to 3, P^(b) removal and coupling to aN-hydroxy imide, deprotection of O-amine, guanidinylation and optionaldeprotection of the guanidine group, is similar to those steps detailedfor the conversion of 23 to 27 in Scheme IIa.

Additionally, compounds of the present invention where Y is NR¹⁰ andR¹—Z is R¹—S₂NR¹⁰— or R¹—CONR¹⁰— can be prepared by Scheme III.Nitroaniline 38 is converted to a sulfonamide by treatment with anappropriate sulfonyl chloride R¹SO₂Cl in the presence of a weak base,such as a tertiary amine. The resulting sulfonamide or carboxamidenitrogen can be alkylated with a suitable alkylating agent R¹⁰L asdescribed in Scheme IIa to provide intermediate 39. Alternatively, 38 istreated with an appropriate acyl chloride (R¹COCl) to provide thecorresponding carboxamide 39. Still alternatively, the carboxamides 39may be produced by the reaction of 38 with carboxylic acids (R¹COOH) byany of the known peptide coupling reagents, such as1,3-dicyclohexylcarbodiimide or Castro's reagent (BOP). After reductionof the nitro group, as described in Scheme IIb, the resulting aniline iscoupled with aldehyde 40 preferably under reductive amination conditionsto give 41. The preferred reducing agent is tetramethylammoniumtriacetoxyborohydride. Alternatively, sodium triacetoxyborohydride orsodium cyanohydride may be used. Still alternatively, reductiveamination may be carried out by forming an imine (Schiff base) betweenthe amine and the carbonyl component using a catalytic amount of acidsuch as p-toluenesulfonic acid, followed by reduction with sodiumborohydride. Still alternatively, the imine may be reduced usingcatalytic hydrogenation using a catalyst such as palladium on carbon instandard solvent such as ethanol. Finally, the O-guanidine protectinggroups, R^(a), R^(b), and R^(c), of 41 may be removed as outlined inScheme Ia to give 42.

As an alternative scheme to produce the O-phthalamide-containingintermediates 9, 16, 26, 31, and 36, the respective phenols 2, 1, 24,28, and 34 may be reacted under basic conditions with reagent 43 whichcontains a leaving group L. This scheme is limited to producingcompounds where R¹² is hydrogen. Reagent 43 is produced by reacting acompound having two leaving groups, L, and L′ under basic conditionswith N-hydroxyphthalimide (Khadilkar and Samant, Indian J. Chem. Sec. B1137 (1993)).

Compounds wherein R^(a) and R^(c) together form a cyclic group, such asan imidazoline, can be synthesized by employing an imidazoline in placeof the aminoguanidine in the above Schemes.

Compounds wherein R⁷ and R¹² or R⁸ and R¹² together form a methylenelinkage can be synthesized by substituting a cyclic ketone having areactive group L that is attached directly or indirectly to thecarbocyclic ring. Examples of suitable reagents include2-hydroxycyclopentanone, 3-hydroxycyclopentanone, 2-hydroxycyclohexanoneand 3-hydroxycyclohexanone.

Compounds VI wherein R⁶ and R^(b) are taken together with the nitrogensto which they are attached to form a ring structure are prepared bysubstituting a heterocyclic amine 12 (below) for the aminoguanidine inthe above Schemes.

Compounds V wherein R⁹ and R^(b) are taken together with the nitrogenatoms to which they are attached to form an imidazoline moiety areprepared by substituting a 2-hydrazinoimidazoline 13 (above) for theaminoguanidines in the above Schemes.

For medicinal use, the pharmaceutically acceptable acid addition salts,those salts in which the anion does not contribute significantly totoxicity or pharmacological activity of the organic cation, arepreferred. The acid addition salts are obtained either by reaction of anorganic base of Formula I with an organic or inorganic acid, preferablyby contact in solution, or by any of the standard methods detailed inthe literature available to any practitioner skilled in the art.Examples of useful organic acids are carboxylic acids such as maleicacid, acetic acid, tartaric acid, propionic acid, fumaric acid,isethionic acid, succinic acid, cyclamic acid, pivalic acid and thelike; useful inorganic acids are hydrohalide acids such as HCl, HBr, HI;sulfuric acid; phosphoric acid and the like. Preferred acids for formingacid addition salts include HCI and acetic acid.

The compounds of the present invention represent a novel class of potentinhibitors of metallo, acid, thiol and serine proteases. Examples of theserine proteases inhibited by compounds within the scope of theinvention include leukocyte neutrophil elastase, a proteolytic enzymeimplicated in the pathogenesis of emphysema; chymotrypsin and trypsin,digestive enzymes; pancreatic elastase, and cathepsin G, achymotrypsin-like protease also associated with leukocytes; thrombin andfactor Xa, proteolytic enzymes in the blood coagulation pathway.Inhibition of thermolysin, a metalloprotease, and pepsin, an acidprotease, are also contemplated uses of compounds of the presentinvention. The compounds of the present invention are preferablyemployed to inhibit trypsin-like proteases.

An end use application of the compounds that inhibit chymotrypsin andtrypsin is in the treatment of pancreatitis. For their end-useapplication, the potency and other biochemical parameters of theenzyme-inhibiting characteristics of the compounds of the presentinvention is readily ascertained by standard biochemical techniques wellknown in the art. Actual dose ranges for their specific end-useapplication will, of course, depend upon the nature and severity of thedisease state of the patient or animal to be treated, as determined bythe attending diagnostician. It is expected that a useful dose rangewill be about 0.01 to 10 mg per kg per day for an effective therapeuticeffect.

Compounds of the present invention that are distinguished by theirability to inhibit either factor Xa or thrombin may be employed for anumber of therapeutic purposes. As factor Xa or thrombin inhibitors,compounds of the present invention inhibit thrombin production.Therefore, these compounds are useful for the treatment or prophylaxisof states characterized by abnormal venous or arterial thrombosisinvolving either thrombin production or action. These states include,but are not limited to, deep vein thrombosis; disseminated intravascularcoagulopathy which occurs during septic shock, viral infections andcancer; myocardial infarction; stroke; coronary artery bypass; fibrinformation in the eye; hip replacement; and thrombus formation resultingfrom either thrombolytic therapy or percutaneous transluminal coronaryangioplasty (PCTA).

Other uses include the use of said thrombin inhibitors as anticoagulantseither embedded in or physically linked to materials used in themanufacture of devices used in blood collection, blood circulation, andblood storage, such as catheters, blood dialysis machines, bloodcollection syringes and tubes, blood lines and stents. The compounds ofthe present invention may also be used as an anticoagulant inextracorporeal blood circuits.

Metal stents have been shown to reduce restenosis, but are thrombogenic.A strategy for reducing the thrombogenicity of stents is to coat, embed,adsord or covalently attach a thrombin-inhibiting agent to the stentsurface. The compounds of the present invention can be employed for thispurpose. Compounds of the invention can be attached to, or embeddedwithin soluble and/or biodegradeable polymers as and thereafter coatedonto stent materials. Such polymers can include polyvinylpyrrolidone,polyhydroxy-propylmethacrylamide-phenol,polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues, polylactic acid, polyglycolic acid,copolymers of polylactic and polyglycolic acid, polyepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates and cross linked or amphipathicblock copolymers of hydrogels. See European Application 761 251,European Application 604,022, Canadian Patent 2,164,684 and PCTPublished Applications WO 96/11668, WO 96/32143 and WO 96/38136.

By virtue of the effects of both factor Xa and thrombin on a host ofcell types, such as smooth muscle cells, endothelial cells andneutrophils, the compounds of the present invention find additional usein the treatment or prophylaxis of adult respiratory distress syndrome;inflammatory responses; wound healing; reperfusion damage;atherosclerosis; and restenosis following an injury such as balloonangioplasty, atherectomy, and arterial stent placement. The compounds ofthe present invention may be useful in treating neoplasia and metastasisas well as neurodegenerative diseases, such as Alzheimer's disease andParkinson's disease.

When employed as thrombin or factor Xa inhibitors, the compounds of thepresent invention may be administered in an effective amount within thedosage range of about 0.1 to about 500 mg/kg, preferably between 0.1 to10 mg/kg body weight, on a regimen in single or 2-4 divided daily doses.

When employed as inhibitors of thrombin, the compounds of the presentinvention may be used in combination with thrombolytic agents such astissue plasminogen activator, streptokinase, and urokinase.Additionally, the compounds of the present invention may be used incombination with other antithrombotic or anticoagulant drugs such as,but not limited to, fibrinogen antagonists and thromboxane receptorantagonists.

Human leucocyte elastase is released by polymorphonuclear leukocytes atsites of inflammation and thus is a contributing cause for a number ofdisease states. Compounds of the present invention are expected to havean anti-inflammatory effect useful in the treatment of gout, rheumatoidarthritis and other inflammatory diseases, and in the treatment ofemphysema. The leucocyte elastase inhibitory properties of compounds ofthe present invention are determined by the method described below.Cathepsin G has also been implicated in the disease states of arthritis,gout and emphysema, and in addition, glomerulonephritis and lunginfestations caused by infections in the lung. In their end-useapplication the enzyme inhibitory properties of the compounds of FormulaI is readily ascertained by standard biochemical techniques that arewell-known in the art.

The Cathepsin G inhibitory properties of compounds within the scope ofthe present invention are determined by the following method. Apreparation of partially purified human Cathepsin G is obtained by theprocedure of Baugh et al., Biochemistry 15: 836 (1979). Leukocytegranules are a major source for the preparation of leukocyte elastaseand cathepsin G (chymotrypsin-like activity). Leukocytes are lysed andgranules are isolated. The leukocyte granules are extracted with 0.20 Msodium acetate, pH 4.0, and extracts are dialyzed against 0.05 M Trisbuffer, pH 8.0 containing 0.05 M NaCl overnight at 4° C. A proteinfraction precipitates during dialysis and is isolated by centrifugation.This fraction contains most of the chymotrypsin-like activity ofleukocyte granules. Specific substrates are prepared for each enzyme,namely N-Suc-Ala-Ala-Pro-Val-p-nitroanilide andSuc-Ala-Ala-Pro-Phe-p-nitroanilide. The latter is not hydrolyzed byleukocyte elastase. Enzyme preparations are assayed in 2.00 mL of 0.10 MHepes buffer, pH 7.5, containing 0.50 M NaCl, 10% dimethylsulfoxide and0.0020 M Suc-Ala-Ala-Pro-Phe-p-nitroanilide as a substrate. Hydrolysisof the p-nitroanilide substrate is monitored at 405 nm and at 25° C.

Useful dose range for the application of compounds of the presentinvention as neutrophil elastase inhibitors and as Cathepsin Ginhibitors depend upon the nature and severity of the disease state, asdetermined by the attending diagnostician, with a range of 0.01 to 10mg/kg body weight, per day, being useful for the aforementioned diseasestates.

Compounds of the present invention that inhibit urokinase or plasminogenactivator are potentially useful in treating excessive cell growthdisease state. As such compounds of the present invention may also beuseful in the treatment of benign prostatic hypertrophy and prostaticcarcinoma, the treatment of psoriasis, and as abortifacients. For theirend-use application, the potency and other biochemical parameters of theenzyme inhibiting characteristics of compounds of the present inventionare readily ascertained by standard biochemical techniques well known inthe art. Actual dose ranges for this application will depend upon thenature and severity of the disease state of the patient or animal to betreated as determined by the attending diagnostician. It is to beexpected that a general dose range will be about 0.01 to 10 mg per kgper day for an effective therapeutic effect.

Additional uses for compounds of the present invention include analysisof commercial reagent enzymes for active site concentration. Forexample, chymotrypsin is supplied as a standard reagent for use inclinical quantitation of chymotrypsin activity in pancreatic juices andfeces. Such assays are diagnostic for gastrointestinal and pancreaticdisorders. Pancreatic elastase is also supplied commercially as areagent for quantitation of α₁-antitrypsin in plasma. Plasmaα₁-antitrypsin increases in concentration during the course of severalinflammatory diseases, and α₁-antitrypsin deficiencies are associatedwith increased incidence of lung disease. Compounds of the presentinvention can be used to enhance the accuracy and reproducibility ofthese assays by titrametric standardization of the commercial elastasesupplied as a reagent. See, U.S. Pat. No. 4,499,082.

Protease activity in certain protein extracts during purification ofparticular proteins is a recurring problem which can complicate andcompromise the results of protein isolation procedures. Certainproteases present in such extracts can be inhibited during purificationsteps by compounds of the present invention, which bind tightly tovarious proteolytic enzymes.

The pharmaceutical compositions of the invention can be administered toany animal that can experience the beneficial effects of the compoundsof the invention. Foremost among such animals are humans, although theinvention is not intended to be so limited.

The pharmaceutical compositions of the present invention can beadministered by any means that achieve their intended purpose. Forexample, administration can be by parenteral, subcutaneous, intravenous,intramuscular, intraperitoneal, transdermal, buccal, or ocular routes.Alternatively, or concurrently, administration can be by the oral route.The dosage administered will be dependent upon the age, health, andweight of the recipient, kind of concurrent treatment, if any, frequencyof treatment, and the nature of the effect desired.

In addition to the pharmacologically active compounds, the newpharmaceutical preparations can contain suitable pharmaceuticallyacceptable carriers comprising excipients and auxiliaries thatfacilitate processing of the active compounds into preparations that canbe used pharmaceutically.

The pharmaceutical preparations of the present invention aremanufactured in a manner that is, itself, known, for example, by meansof conventional mixing, granulating, dragee-making, dissolving, orlyophilizing processes. Thus, pharmaceutical preparations for oral usecan be obtained by combining the active compounds with solid excipients,optionally grinding the resulting mixture and processing the mixture ofgranules, after adding suitable auxiliaries, if desired or necessary, toobtain tablets or dragee cores.

Suitable excipients are, in particular, fillers such as saccharides, forexample, lactose or sucrose, mannitol or sorbitol, cellulosepreparations and/or calcium phosphates,,for example, tricalciumphosphate or calcium hydrogen phosphate, as well as binders, such as,starch paste, using, for example, maize starch, wheat starch, ricestarch, potato starch, gelatin, tragacanth, methyl cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/orpolyvinyl pyrrolidone. If desired, disintegrating agents can be added,such as, the above-mentioned starches and also carboxymethyl-starch,cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a saltthereof, such as, sodium alginate. Auxiliaries are, above all,flow-regulating agents and lubricants, for example, silica, talc,stearic acid or salts thereof, such as, magnesium stearate or calciumstearate, and/or polyethylene glycol. Dragee cores are provided withsuitable coatings that, if desired, are resistant to gastric juices. Forthis purpose, concentrated saccharide solutions can be used, which mayoptionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethyleneglycol, and/or titanium dioxide, lacquer solutions and suitable organicsolvents or solvent mixtures. In order to produce coatings resistant togastric juices, solutions of suitable cellulose preparations, such as,acetylcellulose phthalate or hydroxypropylmethyl-cellulose phthalate,are used. Dye stuffs or pigments can be added to the tablets or drageecoatings, for example, for identification or in order to characterizecombinations of active compound doses.

Other pharmaceutical preparations which can be used orally includepush-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as, glycerol or sorbitol. Thepush-fit capsules can contain the active compounds in the form ofgranules that may be mixed with fillers such as lactose, binders such asstarches, and/or lubricants such as talc or magnesium stearate and,optionally, stabilizers. In soft capsules, the active compounds arepreferably dissolved or suspended in suitable liquids, such as, fattyoils or liquid paraffin. In addition, stabilizers may be added.

Suitable formulations for parenteral administration include aqueoussolutions of the active compounds in water-soluble form, for example,water-soluble salts, alkaline solutions and cyclodextrin inclusioncomplexes. Especially preferred salts are hydrochloride and acetatesalts. One or more modified or unmodified cyclodextrins can be employedto stabilize and increase the water solubility of compounds of thepresent invention. Useful cyclodextrins for this purpose are disclosedin U.S. Pat. Nos. 4,727,064, 4,764,604, and 5,024,998.

In addition, suspensions of the active compounds as appropriate oilyinjection suspensions can be administered. Suitable lipophilic solventsor vehicles include fatty oils, for example, sesame oil, or syntheticfatty acid esters, for example, ethyl oleate or triglycerides orpolyethylene glycol-400 (the compounds are soluble in PEG-400). Aqueousinjection suspensions can contain substances that increase the viscosityof the suspension, for example, sodium carboxymethyl cellulose,sorbitol, and/or dextran. Optionally, the suspension may also containstabilizers.

The following examples are illustrative, but not limiting, of the methodand compositions of the present invention. Other suitable modificationsand adaptations of the variety of conditions and parameters normallyencountered and obvious to those skilled in the art are within thespirit and scope of the invention.

EXAMPLE 13-[3-(2-Chlorophenylsulfonyloxy)-5-methylphenoxy]propoxyguanidine

a) 3-(2-Chlorophenylsulfonyloxy)-5-methylphenol

Orcinol monohydrate (1.42 g, 10 mmol) and 2-chlorobenezenesulfonylchloride (2.43 g, 11 mmol) were mixed in saturated NaHCO₃ (30 mL) anddiethyl ether (30 mL). The biphasic mixture was stirred vigorously andextracted into ethyl acetate (3×50 mL). The organic phase was washedwith brine (2×50 mL) and dried over Na₂SO₄. After removing the solventin vacuo, the residue was purified by flash column chromatography (2%ethyl acetate in dichloromethane) to give the title compound as apale-yellow liquid (2.15 g, 71%). ¹H-NMR (300 MHz, CDCl₃) δ2.22 (s, 3H),5.24 (s, 1H), 6.43 (s, 1H), 6.52 (s, 2H), 7.38 (m, 1H), 7.60 (m, 2H),and 7.96 (dd, 1H,J=3.9, 0.6 Hz).

b) 1-(2-Chlorophenylsulfonyloxy)-3-(3-benzyloxy)propoxy-5-methylbenzene

Diethyl azodicarboxylate (230 μL, 1.46 mmol) was added slowly to asolution of 3-(2-chlorophenylsulfonyloxy)-5-methylphenol (253 mg, 0.866mmol), as prepared in the preceding step, 3-benzyloxypropanol (363 mg,1.24 mmol), and triphenylphosphine (386 mg, (1.47 mmol) indichloromethane (7 mL) at 0° C. The cold bath was removed, and thereaction mixture was stirred at ambient temperature for 3 h. Thereaction mixture was quenched with water (10 mL) and extracted intodiethyl ether (3×20 mL). The combined organic extracts were dried(MgSO₄) and the product purified by flash chromatography (2:1 to 100:0dichloromethane/petroleum ether) to afford the title compound (328.5 mg,85% yield) as a colorless oil. ¹H-NMR (300 MHz, CDCl₃) δ7.95 (dd, 1H,J=7.9, 1.7 Hz), 7.52-7.62 (m, 2H), 7.28-7.38 (m, 6H), 6.58 (br s, 1H),6.54 (br s, 1H), 6.48 (t, 1H, J=1.1 Hz), 4.51 (s, 2H), 3.95 (t, 3H,J=6.2 Hz), 3.62 (t, 2H, J=6.1 Hz), 2.24 (s, 3H), and 2.01 (pentet, 2H,J=6.2 Hz). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acidmatrix) calcd. for C₂₃H₂₃ClO₅S: 469.1 (M+Na). Found: 469.1.

c) 3-[3-(2-Chlorophenylsulfonyloxy)-5-methylphenoxy]propanol

A mixture of1-(2-chlorophenylsulfonyloxy)-3-(3-benzyloxy)propoxy-5-methylbenzene(328.5 mg, 0.736 mmol), as prepared in the preceding step, 66 mg of 10%palladium on carbon, and 180 μL (0.72 mmol) of 4 N HCl/dioxane in 5 mLof tetrahydrofuran was hydrogenated (atmospheric pressure) at ambienttemperature for 1 h. The reaction was hydrogenated through Celite 545and then concentrated. Purification by flash chromatography usingelutions of 2-10% diethyl ether/dichloromethane gave 217 mg (83% yield)of the title compound as an oil. ¹H-NMR (300 MHz, CDCl₃) δ7.97 (dd, 1H,J=7.8, 1.4 Hz), 7.56-7.65 (m, 2H), 7.36-7.41 (m, 1H), 6.60 (br s, 1H),6.54 (br s, 1H), 6.50 (t, 1H, J=2 Hz), 4.03 (t, 2H, J=4.7 Hz), 3.92 (s,1H), 3.82 (q, 2H, J=6.7 Hz), 2.24 (s, 3H), and 1.99 (pentet, 2H, J=6Hz).

d)N-[3-[3-(2-Chlorophenylsulfonyloxy)-5-methylphenoxy]propoxy]phthalimide

Diethyl azodicarboxylate (4.0 mL, 0.024 mol) was added dropwise to asolution of 3-[3-(2-chlorophenylsulfonyloxy)-5-methylphenoxy]propanol(8.5 g, 0.024 mol), as prepared in the preceding step,triphenylphosphine (6.26 g, 0.024 mol), and N-hydroxyphthalimide (4.01g, 0.024 mol) in anhydrous tetrahydrofuran (240 mL). The solution wasallowed to stir at ambient temperature overnight. The tetrahydrofuranwas evaporated, and the residue was purified by silica gelchromatography. Elution was carried out using a gradient of 50%dichloromethane in hexane to 100% dichloromethane. The appropriatefractions were combined, evaporated to dryness, and placed under highvacuum to give 6.5 g (54% yield) of an oil. Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₂₄H₂₀ClNO₇S: 524.1(M+Na). Found: 524.2.

e) 3-[3-(2-Chlorophenylsulfonyloxy)-5-methylphenoxy]propoxyamine

A suspension ofN-[3-(2-chlorophenylsulfonyloxy)-5-methylphenoxy]propoxy]phthalimide 6.5g, 0.013 mol), as prepared in the preceding step, in 2-propanol/water(6:1; 690 mL) was treated with sodium borohydride (2.46 g, 0.065 mol).The reaction mixture was stirred at ambient temperature for 2 days. Thereaction mixture was quenched with 2N hydrochloric acid, and the mixturewas warmed at 50° C. for 2 hours. The reaction mixture was cooled in anice:water bath and adjusted to pH 8.0 with 2 N sodium hydroxide. The2-propanol was evaporated on a rotary evaporator, and the residualaqueous solution was extracted with ethyl acetate (3×75 mL). Thecombined ethyl acetate extracts were washed with brine, dried overanhydrous sodium sulfate, and evaporated to dryness. The material waspurified by silica gel chromatography by elution with a gradient of 50%dichloromethane/hexane to 100% dichloromethane, followed by 90%dichloromethane/10% acetonitrile. The appropriate fractions werecombined and evaporated to an oil, which crystallized under high vacuumto give 4.1 g (85% yield) of the title compound. ¹H-NMR (300 MHz, CDCl₃)δ7.97 (dd, J=7.9, 1.5 Hz, 1H), 7.55-7.65 (m, 2H), 7.37 (td, J=7.8, 1.6Hz, 1H), 6.59 (br s, 1H), 6.53 (m, 1H), 6.49 (t, J=2.2 Hz, 1H), 5.39 (brd, 2H), 3.92 (t, J=6.3 Hz, 2H), 3.79 (t, J=6.2 Hz, 2H), 2.24 (s, 3H),and 2.00 (pentet, J=6.2 Hz, 2H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₆H₁₈ClNO₅S: 372.1(M+H). Found: 371.5.

f) 3-[3-(2-Chlorophenylsulfonyloxy)-5-methylphenoxy]propoxyguanidine

A solution of3-[3-(2-chlorophenylsulfonyloxy)-5-methylphenoxy]propoxyamine (0.43 g,0.0012 mol), as prepared in the preceding step, in anhydrousN,N-dimethylformamide (15 mL) was treated with 1H-pyrazole-1-carboxamidine hydrochloride (0.34 g, 0.0034 mol). Thereaction mixture was stirred overnight at ambient temperature. Anadditional 100 mg of 1H -pyrazole-1-carboxamidine hydrochloride wasadded, and the reaction mixture was stirred at ambient temperatureovernight. The reaction mixture was evaporated to dryness under highvacuum. The residue was treated with acetonitrile, and the resultingcrystalline material was collected by filtration and discarded. Thefiltrate was evaporated to dryness and partitioned between ether andwater. The aqueous layer was washed with ether (4×25 mL). The aqueouslayer was separated and basified with 2N sodium hydroxide, and theresultant aqueous layer was extracted with ethyl acetate (4×50 mL). Thecombined ethyl acetate extracts were washed with brine, dried, andevaporated to give 0.46 g of the title compound as an oil. ¹H-NMR (300MHz, CDCl₃) δ7.94 (d, J=7.6 Hz, 1H), 7.54-7.62 (m, 2H), 7.34-7.40 (m,1H), 6.57 (br s, 1H), 6.48 (m, 2H), 5.75 (br m, 2H), 3.96 (t, J=6.2 Hz,4H), 2.21 (s, 3H), and 2.05 (pentet, J=6.2 Hz, 2H). Mass spectrum(MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₁₇H₂₀ClN₃O₅S: 4.14.1 (M+H). Found: 4.14.2

EXAMPLE 23-[3-(2-Methoxyphenylsulfonyloxy)-5-methylphenoxy]propoxyguanidine

a) 3-(5-Chloro-2-methoxyphenylsulfonyloxy)-5-methylphenol

Saturated aqueous NaHCO₃ (70 mL) was added to a solution of5-chloro-2-methoxynenzensulfonyl chloride (3.83 g, (15.9 mmol andorcinol monohydrate (3.39 g, 23.9 mmol) in di-n-butyl ether (53 mL) andtetrahydrofuran (17 mL). The biphasic solution was mixed vigorously at50° C. for 7 h then at ambient temperature overnight. The reactionmixture was combined with that from a previous reaction (which used 4.53g 18.8 mmol of 5-chloro-2-methoxybenzenesulfonyl chloride), the layerswere separated, and the aqueous layer was extracted with ethyl acetate(2×100 mL). The combined organic extracts were washed with brine (250mL), dried over Na₂SO₄, filtered, and evaporated to give 18.25 g of aclear brown oil. The product was purified by flash column chromatography(1% to 4% ethyl acetate in dichloromethane) to give the title compound(9.86 g, 86%) as a pale yellow oil which crystallized upon standing.¹H-NMR (300 MHz, CDCl₃) (7.81 (d, 1H, J=2.6 Hz), 7.55 (dd, 1H, J=8.9,2.6 Hz), 7.02 (d, 1H, J=8.9 Hz), 6.53 (m, 2H), 6.41 (t, 1H, J=2.2 Hz),3.99 (s, 3H), 2.24 (s, 3H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₄H₁₃ClO₅S: 351.0(M+Na). Found: 351.1.

b) 3-(2-Methoxyphenylsulfonyloxy)-5-methylphenol

4-Methylmorpholine (3.2 mL, 29.1 mmol) was added to a mixture of3-(5-chloro-2-methoxyphenylsulfonyloxy)-5-methylphenol (8.82 g, 26.8mmol, prepared in the preceding step) and 10% palladium on carbon(2.23g) in deoxygenated methanol (15 mL). The mixture was stirred at ambienttemperature under hydrogen (balloon) for 3 h, then filtered throughCelite (drafomaceous earth) with methanol. Solvent was removed in vacuoand crude product was purified by flash column chromatography (CH₂Cl₂ to5% ethyl acetate in dichloromethane) to give the title compound (4.97 g,63%) as a colorless syrup. ¹H-NMR (300 MHz, DMSO-d₆) (9.71 (s, 1H), 7.76(ddd, 1H, J=8.4, 7.4, 1.7 Hz), 7.69 (dd, 1H, J=7.9, 1.7 Hz), 7.38 (d,1H, J=8.4 Hz), 7.09 (dt, 1H, J=7.9, 1.0 Hz), 6.48 (br s, 1H), 6.33 (brs, 1H), 6.26 (t, 1H, J=2.2 Hz), 4.00 (s, 3H), 2.15 (s, 3H). Massspectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₁₄H₁₄O₅S: 317.0 (M+Na). Found: 316.9.

c) 3-[3-(2-Methoxyphenylsulfonyloxy)-5-methylphenoxy]propanol

Tri-n-butylphosphine (8.4 mL, 34 mmol) was added dropwise over 5 min to3-(2-methoxyphenylsulfonyloxy)-5-methylphenol (4.97 g, 16.9 mmol,prepared in the preceding step), 1,3-propanediol (12 mL, 170 mmol) and1,1′-(azodicarbonyl)dipiperidine (8.54 g, 33.8 mmol) in anhydroustetrahydrofuran (75 mL) at 0° C. under a nitrogen atmosphere.Dichloromethane (75 mL) was added mid-way through thetri-n-butylphosphine addition to aid stirring. The slurry was stirred atambient temperature for 1 h, then the mixture was cooled to 0° C. andadditional 1,1′-(azodicarbonyl)dipiperidine (4.27 g, 16.9 mmol) andtri-n-butylphosphine (4.2 mL, 16.9 mmol) were added. The reaction wasstirred overnight at ambient temperature. Diethyl ether (200 mL) wasadded and the mixture was filtered. The filtrate was concentrated invacuo, and the residue was purified by flash column chromatography (25%ethyl acetate in hexane to 60% ethyl acetate in hexane, then 2% acetonein dichloromethane to 7% acetone in dichloromethane in two separatechromatographic separations) to give the title compound (3.79 g, 64%) asa gold oil. ¹H-NMR (300 MHz, CDCl₃) δ7.82 (dd, 1H, J=7.9, 1.7 Hz), 7.61(ddd, 1H, J=8.4, 7.5, 1.8 Hz), 7.08 (d, 1H, J=8.4 Hz), 7.01 (ddd, 1H,J=7.9, 7.5, 1 Hz), 6.58 (br s, 1H), 6,51 (br s, 1H), 6.46 (t, 1H, J=2.1Hz), 4.02 (s, 3H), 4.00 (t, 2H, J=6.0 Hz), 3.81 (dt, 2H, J=5.7, 5.3 Hz),2.24 (s, 3H), 1.98 (pentet, 2H, J=6.0 Hz), 1.72 (t, 1H, J=5.0 Hz). Massspectrum (MALDI-TOF, (α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₁₇H₂₀O₆S: 375.1 (M+Na). Found: 375.1.

d)N-[3-[3-(2-Methoxyphenylsulfonyloxy)-5-methylphenoxy]propoxy]phthalimide

Diethyl azodicarboxylate (67 (L, 0.40 mmol) was added dropwise over 5.5min to 3-[3-(2-methoxyphenylsulfonyloxy)-5-methylphenoxy]propanol (118mg, 0.33 mmol, prepared in the preceding step), triphenylphosphine (106mg, 0.40 mmol), and N-hydroxyphthalimide (55 mg, 0.33 mmol) in anhydroustetrahydrofuran (3 mL) at 0° C. under a nitrogen atmosphere. Thesolution was stirred at 0° C. for an additional 20 min then at ambienttemperature overnight. The reaction mixture was concentrated, and theresidue was purified by flash column chromatography (dichloromethane) togive the title compound (116 mg, 69%) as a colorless resin. ¹H-NMR (300MHz, CDCl₃) (7.88-7.73 (m, 5H), 7.61 (ddd, 1H, J=8.4, 7.4, 1.7 Hz), 7.10(d, 1H, J=8.4 Hz), 7.01 (dt, 1H, J=7.7, 0.9 Hz), 6.60 (br s, 1H), 6.56,(br s, 1H), 6.42 (t, 1H, J=2.2 Hz), 4.36 (t, 2H, J=6.2 Hz), 4.09 (t, 2H,J=6.2 Hz), 4.04 (s, 3H), 2.25 (s, 3H), 2.18 (pentet, 2H, J=6.2 Hz). Massspectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₂₅H₂₃NO₈S: 520.1 (M+Na). Found: 520.2.

e) 3-[3-(2-Methoxyphenylsulfonyloxy)-5-methylphenoxy]propoxyamine

A mixture of sodium borohydride (45 mg, 1.1 mmol) andN-[3-[3-(2-methoxyphenylsulfonyloxy)-5-methylphenoxy]propoxy]phthalimide(113 mg, 0.23 numol, prepared in the preceding step) in 2-propanol (12mL) and water (2 mL) was stirred overnight at ambient temperature. Thereaction mixture was adjusted to pH 1 aqueous HCl (3.5 mL, 2N), and thesolution was stirred at 50° C. for 2 h. The solution was cooled to 0° C.and adjusted to pH 12 with 2N NaOH. The solution was stirred at ambienttemperature for 2 h, then 2-propanol was removed by rotary evaporation.The resulting mixture was extracted with ethyl acetate (2×30 mL). Thecombined organic extracts were washed with brine (40 mL), dried overNa₂SO₄, filtered, and evaporated to give the title compound (79 mg, 95%)as a colorless oil. ^(1 H-NMR ()300 MHz, CDCl₃) (7.82 (dd, 1H, J=7.9,1.7Hz), 7.61 (ddd, 1H, J=8.4, 7.5, 1.8 Hz), 7.08 (dd, 1H, J=8.4, 0.8 Hz),7.00 (ddd, 1H, J=8, 7.5, 1 Hz), 6.58 (br s, 1H), 6.50 (br s, 1H), 6.45(t, 1H, J=2.1 Hz), 5.38 (br s, 2H), 4.02 (s, 3H), 3.92 (t, 2H, J=6.3Hz), 3.79 (t, 2H, J=6.2 Hz), 2.23 (s, 3H), 2.00 (pentet, 2H, J=6.2 Hz).Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd.for C₁₇H₂₁NO₆S: 390.1 (M+Na). Found: 390.1.

f) 3-[3-(2-Methoxyphenylsulfonyloxy)-5-methylphenoxy]propoxyguanidine

A solution of3-[3-(2-methoxyphenylsulfonyloxy)-5-methylphenoxy]propoxyamine (74 mg,0.20 mmol, prepared in the preceding step) and1H-pyrazole-1-carboxamidine hydrochloride (60 mg, 0.41 mmol) inanhydrous N,N-dimethylformamide (2 mL) was stirred at ambienttemperature overnight. Additional 1H-pyrazole-1-carboxamidinehydrochloride (30 mg, 0.20 mmol) was added, and the reaction was stirredat ambient temperature for 3 days. N,N-Dimethylformamide was removed invacuo, then the residue was treated with acetonitrile. The mixture wasfiltered to remove excess 1H-pyrazole-1-carboxamidine hydrochloride, andthe filtrate was concentrated in vacuo. The residual oil was partitionedbetween diethyl ether (10 mL) and water (10 mL). The aqueous layer waswashed with diethyl ether (2×10 mL), adjusted to pH 8 with 2N NaOH, andextracted with ethyl acetate (2×10 mL). The ethyl acetate extracts werewashed with pH 7 buffer (2×15 mL) and brine (15 mL), dried over Na₂SO₄,filtered, and evaporated to give the title compound (64 mg, 78%) as acolorless oil. ¹H-NMR (300 MHz, DMSO-d₆) δ7.76 (ddd, 1H, J=8.4, 7.4, 1.8Hz), 7.69 (dd, 1H, J=7.9, 1.6 Hz), 7.37 (d, 1H, J=7.7 Hz), 7.09 (dt, 1H,J=7.9, 1.0 Hz), 6.69 (s, 1H), 6.47 (s, 1H), 6.33 (t, 1H, J=2.1 Hz), 4.00(s, 3H), 3.92 (t, 2H, J=6.5 Hz), 3.70 (t, 2H, J=6.1 Hz), 2.20 (s, 3H),1.88 (pentet, 2H, J=6.3 Hz). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₈H₂₃N₃O₆S: 410.1(M+H), 432.1 (M+Na). Found: 410.1, 432.6.

EXAMPLE 33-[5-Methyl-3-(quinolinyl-8-sulfonyloxy)phenoxy]propoxyguanidinehydrochloride

a) -Methyl-3-(quinolinyl-8-sulfonyloxy)phenol

A mixture of orcinol monohydrate (4.0 g, 28 mmol) and8-quinolinesulfonyl chloride (6.1 g, 26.7 mmol) in diethyl ether (120mL) and saturated sodium bicarbonate (120 mL) was vigorously stirred atambient temperature for 4 days. The reaction mixture was extracted intoethyl acetate, dried (MgSO₄), and concentrated. Crystallization fromdiethyl ether/ethyl acetate/hexane gave 4.48 g (50%) of the titlecompound as a tan powder. ¹H-NMR (300 MHz, DMSO-d₆) δ9.62 (br s, 1H),9.23 (dd, 1H, J=4, 2 Hz), 8.63 (dd, 1H, J=8, 2 Hz), 8.45 (dd, 1H, J=8, 2Hz), 8.36 (1H, J=8, 2 Hz), 7.74-7.83 (m, 2H), 6.44 (br s, 1H), 6.29 (brs, 1H), 6.10 (t, 1H, J=2 Hz), 2.09 (s, 3H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₆H₁₃NO₄S: 316.1(M+H), 338.0 (M+Na). Found 316.0, 338.1.

b) 3-[5-Methyl-3-(quinolinyl-8-sulfonyloxy)phenoxy]propanol

To 5-methyl-3-(quinolinyl-8-sulfonyloxy)phenol (3.0 g, 9.0 mmol), asprepared in the preceding step 1,3-propanediol (4 mL, 55.2 mmol), and1,1′-(azodicarbonyl)dipiperidine (3.42 g, 13.6 mmol) at 0° C. intetrahydrofuran (60 mL) was added slowly tri-n-butylphosphine (3.36 mL,13.5 mmol). The cold bath was removed, and the reaction mixture wasstirred at ambient temperature overnight. The TLC analysis showedstarting material. To the reaction mixture was added sequentially1,1′-(azodicarbonyl)dipiperidine (1.9 g) and tri-n-butylphosphine (1.7mL). The reaction mixture was stirred at ambient temperature for 2 h.The reaction mixture was then diluted with diethyl ether and theresulting suspension filtered. The filtrate was concentrated andpurified directly by flash chromatography using elutions ofdichloromethane/ethyl acetate (3:1 then 2:3) to give 3.19 g (95% yield)of the title compound as an oil. ¹H-NMR (300 MHz, CDCl₃) δ9.27 (dd, 1H,J=4, 2 Hz), 8.41 (dd, 1H, J=7, 2 Hz), 8.31 (dd, 1H, J=8, 2 Hz), 8.14(dd, 1H, J=7, 2 Hz), 7.61-7.65 (m, 2), 6.54 (br s, 1H), 6.49 (br s, 1H),6.42 (t, 1H, J=2 Hz), 3.92 (t, 2H, J=6 Hz), 3.77 (t, 2H), 2.17 (s, 3H).Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd.for C₁₉H₁₉NO₅S: 374.1 (M+H), 3.96.1 (M+Na). Found: 374.0, 396.2.

c)N-[3-[5-Methyl-3-(quinolinyl-8-sulfonyloxy)phenoxy]propoxy]phthalimide

Diethyl azodicarboxylate (136 μL, 0.81 mmol) was added dropwise over 7min to 3-[5-methyl-3-(quinolinyl-8-sulfonyloxy)phenoxy]propanol (252 mg,0.68 mmol, prepared in the preceding step), N-hydroxyphthalimide (11 mg,0.68 mmol), and triphenylphosphine (213 mg, 0.81 mmol) in anhydroustetrahydrofuran (6 mL) at 0° C. under a nitrogen atmosphere. Thesolution was stirred at 0° C. for 1 h then at ambient temperature for 3days. Solvent was removed in vacuo, and the crude product was purifiedby flash column chromatography (100% dichloromethane to 1% acetone indichloromethane) to give the title compound (332 mg, 92%) as a colorlessfoam. ¹H-NMR (300 MHz, CDCl₃) δ9.28 (dd, 1H, J=4.2, 1.8 Hz), 8.43 (dd,1H, J=7.4, 1.4 Hz), 8.30 (dd, 1H, J=8.4, 1.7 Hz), 8.14 (dd, 1H, J=8.3,1.3 Hz), 7.85-7.75 (m, 4H), 7.63 (d, 1H, J=8.3 Hz), 7.61 (dd, 1H, J=8.2,3.2 Hz), 6.56 (br s, 1H), 6.53 (br s, 1H), 6.36 (br s, 1H), 4.31 (t, 2H,J=6.2 Hz), 3.98 (t, 2H, J=6.2 Hz), 2.19 (s, 3H), 2.11 (pentet, 2H, J=6.2Hz). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix)calcd. for C₂₇H₂₂N₂O₇S: 519.1 (M+H), 541.1 (M+Na). Found: 518.7, 540.8.

d) 3-[5-Methyl-3-(quinolinyl-8-sulfonyloxy)phenoxy]propoxyamine

Sodium borohydride (107 mg, 2.8 mmol) was added toN-[3-[5-methyl-3-(quinolinyl-8-sulfonyloxy)phenoxy]propoxy]phthalimide(292 mg, 0.56 mmol, prepared in the preceding step) in 2-propanol (10mL), tetrahydrofuran (1.7 mL) and water (1.7 mL). Hydrogen gas wasevolved for 40 min. The mixture was stirred overnight at ambienttemperature. Aqueous HCl (8.4 mL, 2N) was added dropwise (hydrogen wasevolved), and the solution was heated at 50° C. for 2 h. The solutionwas cooled to 0° C. and adjusted to pH 10 with 2N NaOH. Organic solventwas removed in vacuo, and the residual mixture was extracted with ethylacetate (2×30 mL). The combined organic extracts were washed with brine(50 mL), dried over Na₂SO₄, filtered, and evaporated to give a pale goldoil. Crude product was purified by flash column chromatography (60:40 to80:20 ethyl acetate/hexane) to give the title compound (166 mg, 76%).¹H-NMR (300 MHz, CDCl₃) (9.27 (dd, 1H, J=4.3, 1.8 Hz), 8.42 (dd, 1H,J=7.4, 1.5 Hz), 8.30 (dd, 1H, J=8.3, 1.8 Hz), 8.14 (dd, 1H, J=8.2, 1.5Hz), 7.63 (d, 1H, J=8.2 Hz), 7.61 (dd, 1H, J=8.3, 3.5 Hz), 6.53 (br s,1H), 6.47 (br s, 1H), 6.41 (t, 1H, J=2 Hz), 5.37 (br s, 2H), 3.83 (t, 2H, J=6.3 Hz), 3.75 (t, 2 H, J=6.2 Hz), 2.17 (s, 3 H), 1.94 (pentet, 2H,J=6.2 Hz). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acidmatrix) calcd. for C₁₉H₂₀N₂O₅S: 389.1 (M+H), 411.1 (M+Na). Found: 388.7,410.9.

e) 3-[5-Methyl-3-(quinolinyl-8-sulfonyloxy)phenoxy]propoxyguanidinehydrochloride

A solution of3-[5-methyl-3-(quinolinyl-8-sulfonyloxy)phenoxy]propoxyamine (162 mg,0.42 mmol, prepared in the preceding step) and1H-pyrazole-1-carboxamidine hydrochloride (184 mg, 1.25 mmol) inanhydrous N,N-dimethylformamide (2.0 mL) was stirred at ambienthydrochloride (61.4 mg, 0.42 mmol) was added, and stirring was continuedovernight. N,N-Dimethylformamide was removed in vacuo, then acetonitrile(5 mL) was added, and the solution was cooled to 0° C. to crystallizeexcess 1H-pyrazole-1-carboxamidine hydrochloride. The mixture wasfiltered and the filtrate was concentrated in vacuo to give a palegold-brown oil. Crude product was dissolved in water (15 mL) andextracted with diethyl ether (2×15 mL). The aqueous layer wasneutralized (pH 7) with 2N NaOH and extracted with ethyl acetate (2×15mL). The combined ethyl acetate extracts were washed with pH 7 buffer(2×15 mL) and brine (15 mL), dried over Na₂SO₄, filtered, and evaporatedto give the free base of the title compound (147 mg, 82%) as a colorlessoil.

The title compound was made by adding a solution of the free base,3-[5-methyl-3-(quinolinyl-8-sulfonyloxy)phenoxy]propoxyguanidine, (143mg, 0.33 mmol, prepared above) in ethanol (1 mL) to ethanolic HCl (1.06mL, 1.1 M, 1.2 mmol) in anhydrous diethyl ether (100 mL). Filtrationunder nitrogen gave the title compound (120 mg, 77%) as a hygroscopicyellow solid. ¹H-NMR (300 MHz, DMSO-d₆) δ9.23 (dd, 1H, J=4.2, 1.8 Hz),8.64 (dd, 1H, J=8.4, 1.8 Hz), 8.47 (dd, 1H, J=8.3, 1.4 Hz), 8.38 (dd,1H, J=7.4, 1.4 Hz), 7.81 (dd, 1H, J=8, 4.2 Hz), 7.80 (d, 1H, J=8 Hz),6.66 (br s, 1H), 6.40 (br s, 1H), 6.34 (t, 1H, J=2.2 Hz), 3.87 (q, 4H,J=6 Hz), 2.14 (s, 3H), 1.95 (pentet, 2H, J=6 Hz). Mass spectrum(MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₂₀H₂₂N₄O₅S: 431.1 (M+H). Found: 430.9.

EXAMPLE 43-[3-(5-Chloro-2-methoxyphenylsulfonyloxy)-5-methylphenoxy]propoxyguanidinehydrochloride

a) 3-[3-(5-Chloro-2-methoxyphenylsulfonyloxy)-5-methylphenoxy]propanol

Tri-n-butylphosphine (7.6 mL) 30.4 mmol) was added dropwise over 20 minto 3-(5-chloro-2-methoxyphenylsulfonyloxy)-5-methylphenol (5.00 g, 15.2mmol, prepared in step a of Example 2), 1,3-propanediol (3.3 mL, 45.6mmol) and 1,1′-(azodicarbonyl)dipiperidine (7.68 g, 30.4 mmol) inanhydrous tetrahydrofuran (80 mL) at 0° C. under a nitrogen atmosphere.Dichloromethane (150 mL) was added mid-way through thetri-n-butylphosphine addition to aid stirring. The slurry was stirredfor an additional 5 min at 0° C. then at ambient temperature for 3 h.Diethyl ether (400 mL) was added, and the mixture was stirred for 10 minthen filtered. The filtrate was concentrated and the product waspurified by flash column chromatography (25% to 60% ethyl acetate inhexane) to give the title compound (4.07 g, 69%) as a gold oil. ¹H-NMR(300 MHz, CDCl₃) (7.82 (d, 1H, J=2.8 Hz), 7.56 (dd, 1H, J=8.9, 2.6 Hz),7.03 (d, 1H, J=8.9 Hz), 6.62 (br s, 1H), 6.52 (br s, 1H), 6.47 (t, 1H,J=2.3 Hz), 4.03 (t, 2H, J=6 Hz), 4.01 (s, 3H), 3.85-3.80 (m, 2H), 2.26(s, 3H), 2.00 (pentet, 2H, J=6 Hz), 1.64 (t, 1H, J=5 Hz). Mass spectrum(MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₁₇H₁₉ClO₆S: 409.0 (M+Na). Found: 409.0.

b)N-[3-[3-(5-Chloro-2-methoxyphenylsulfonyloxy)-5-methylphenoxy]propoxy]phthalimide

Diethyl azodicarboxylate (0.16 mL, 0.95 mmol) was added dropwise over 6min to3-[3-(5-chloro-2-methoxyphenylsulfonyloxy)-5-methylphenoxy]propanol(0.31 g, 0.79 mmol, prepared in the preceding step), triphenylphosphine(0.25 g, 0.93 mmol) and N-hydroxyphthalimide (0.13 g, 0.80 mmol) inanhydrous tetrahydrofuran (7.9 mL) at 0° C. under a nitrogen atmosphere.The solution was stirred 0° C. for an adddional 15 min then at ambienttemperature overnight. The reaction mixture was concentrated, and thecrude product was purified by flash column chromatography (1% acetone indichloromethane) to give the title compound (0.417 g, 99%) as acolorless foam. ¹H-NMR (300 MHz, CDCl₃) δ7.88-7.75 (m, 5H), 7.56 (dd,1H, J=8.9, 2.7 Hz), 7.05 (d, 1H, J=8.9 Hz), 6.64 (br s, 1H), 6.57 (br s,1H), 6.43 (t, 1H, J=2 Hz), 4.37 (t, 2H, J=6.1 Hz), 4.12 (t, 2H, J=6.2Hz), 4.03 (s, 3H), 2.28 (s, 3H), 2.19 (pentet, 2H, J=6.1 Hz). Massspectrum (MALDI-TOF, gentisic acid matrix) calcd. for C₂₅H₂₂ClNO₈S:554.1 (M+Na). Found: 553.7.

c)3-[3-(5-Chloro-2-methoxyphenylsulfonyloxy)-5-methylphenoxy]propoxyamine

Sodium borohydride (145 mg, 3.84 mmol) was added to a solution ofN-[3-[3-(5-chloro-2-methoxyphenylsulfonyloxy)-5-methylphenoxy]propoxy]phthalimide(407 mg, 0.76 mmol, prepared in the preceding step) in 2-propanol (25mL), tetrahydrofuran (5 mL), and water (4 mL). Hydrogen was evolved for20 min. The mixture was stirred overnight at ambient temperature.Aqueous HCl (11.4 mL, 2N, 22.8 mmol) was added dropwise; hydrogen wasevolved. The solution was stirred at 50° C. for 2 h, cooled to 0° C.,and adjusted to pH 10 with 2N NaOH. Organic solvent was removed byrotary evaporation at ambient temperature, and the resulting mixture wasextracted with ethyl acetate (2×30 mL). The combined organic extractswere washed with brine (50 mL), dried over Na₂SO₄, filtered, andevaporated to give 365 mg of a colorless oil. Crude product was purifiedby flash column chromatography (50% ethyl acetate in hexane to 100%ethyl acetate) to give the title compound (265 mg, 86%) as a colorlessoil. ¹H-NMR (300 MHz, CDCl₃) (7.82 (d, 1H, J=2.6 Hz), 7.56 (dd, 1H,J=8.9, 2.6 Hz), 7.03 (d, 1H, J=8.9 Hz), 6.60 (br s, 1H), 6.51 (br s,1H), 6.46 (t, 1H, J=2.2 Hz), 5.39 (br s, 2H), 4.01 (s, 3H), 3.95 (t, 2H,J=6.3 Hz), 3.80 (t, 2H, J=6.2 Hz), 2.26 (s, 3H), 2.02 (pentet, 2H,J=6.2). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix)calcd. for C₁₇H₂₀ClNO₆S: 402.1 (M+H), 424.1 (M+Na). Found: 401.6, 423.9.

d)3-[3-(5-Chloro-2-methoxyphenylsulfonyloxy)-5-methylphenoxy]propoxyguanidinehydrochloride

A mixture of3-[3-(5-chloro-2-methoxyphenylsulfonyloxy)-5-methylphenoxy]propoxyamine(265 mg, 0.66 mmol, prepared in the preceding step) and1H-pyrazole-1-carboxamidine hydrochloride (196 mg, 1.33 mmol) inanhydrous N,N-dimethylformamide (3 mL) was stirred at ambienttemperature for 2.5 h. Additional 1H-pyrazole-1-carboxamidinehydrochloride (97 mg, 0.66 mmol) was added and the reaction was stirredat ambient temperature for 3 days. N,N-Dimethylformamide was removed invacuo, then acetonitrile (1 mL) was added to precipitate excess1H-pyrazole-1-carboxamidine hydrochloride. The mixture was filtered andthe filtrate was concentrated in vacuo. The residual oil was partitionedbetween diethyl ether (20 mL) and water (20 mL). The aqueous layer waswashed with diethyl ether (2×20 mL). The aqueous layer was neutralized(pH 7) with 2N NaOH and extracted with ethyl acetate (2×30 mL). Theethyl acetate extracts were washed with pH 7 buffer (2×20 mL) and brine(30 mL), dried over Na₂SO₄, filtered, and evaporated to give the freebase of the title compound (281 mg, 96%) as a colorless oil. Massspectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₁₈H₂₂CIN₃O₆S: 444.1 (M+H), 466.1 (M+Na). Found 444.6, 466.7.

The hydrochloride salt of the title compound was made by adding asolution of the free base,3-[3-(5-chloro-2-methoxyphenylsulfonyloxy)-5-methylphenoxy]propoxyguanidine,(261 mg, 0.59 mmol) in 2-propanol (6 mL) to diethyl ether (100 mL)containing HCl in ethanol (1.1 mL of a 1.1 M solution, 1.2 mmol).Solvent was removed in vacuo to give the title compound (285 mg) as acolorless oil. ¹H-NMR(300 MHz, DMSO-d6) (7.86 (dd, 1H, J=9.0, 2.7 Hz),7.65 (d, 1H, J=2.7 Hz), 7.44 (d, 1H, J=9.0 Hz), 6.74 (br s, 1H), 6.49(br s, 1H), 6.43 (br s, 1H), 4.01 (s, 3H), 4.00 (t, 2H, J=6.4 Hz), 3.91(t, 2H, J=6.3 Hz), 2.23 (s, 3H), 2.02 (pentet, 2H, J=6.3 Hz). Massspectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₁₈H₂₂ClN₃O₆S: 444.1 (M+H). Found 443.5.

EXAMPLE 53-[3-(5-Chlorothiophenyl-2-sulfonyloxy)-5-methylphenoxy]propoxyguanidinehydrochloride

a) 3-(5-Chlorothiophenyl-2-sulfonyloxy)-5-methylphenol

A mixture of orcinol monohydrate (5.0 g, 35.2 mmol), and5-chlorothiopene-2-sulfonyl chloride (7.64 g, 35.2 mmol) in 50 mL ofsaturated sodium bicarbonate, 50 mL of diethyl ether, and 15 mL oftetrahydrofuran was stirred at 60° C. for 2 h and then at 40° C.overnight. The reaction mixture was extracted into diethyl ether, dried(MgSO₄), and passed through a thick pad of silica gel (ca. 500 mL) usingelutions of dichloromethane and then 3% diethyl ether/dichloromethane toprovide 5.49 g (51%) of the title compound as a pale orange oil. ¹H-NMR(300 MHz, CDCl₃) δ7.40 (d, 1H, J=4 Hz), 6.94 (d, 1H, J=4 Hz), 6.59 (brs, 1H), 6.49 (br s, 1H), 6.40 (t, 1H, J=2 Hz), 5.38 (s, 1H), 2.26 (s,3H). Mass spectrum (MALDI-TOF gentisic acid matrix) calcd. forC₁₁H₉ClO₄S₂: 327.0 (M+Na). Found: 327.0.

b) 3-[3-(5-Chlorothiophenyl-2-sulfonyloxy)-5-methylphenoxy]propanol

Tri-n-butylphosphine (6.1 mL, 24 mmol) was added dropwise over 5 min to3-(5-chlorothiophenyl-2-sulfonyloxy)-5-methylphenol (3.49 g, 11.5 mmol,prepared in the preceding step), 1,3-propanediol (2.2 mL, 30 mmol) and1,1′-(azodicarbonyl)dipiperidine 6.16 g, 24 mmol) in anhydrous THF (45mL) at 0° C. under a nitrogen atmosphere. Dichloromethane (70 mL) andadditional tetrahydrofuran (10 mL) were added mid-way through thetri-n-butylphosphine addition to aid stirring. The slurry was stirred atambient temperature for 2.5 h, then diethyl ether (300 mL) was added andthe mixture was filtered. The filtrate was concentrated, and the residuewas purified by flash column chromatography (25% to 40% ethyl acetate inhexane) to give the title compound (3.11 g, 75%) as a gold oil. ¹H-NMR(300 MHz, CDCl₃) (7.41 (d, 1H, J=4.1 Hz), 6.95 (d, 1H, J=4.1 Hz), 6.66(br s, 1H), 6.50 (br s, 1H), 6.45 (t, 1H, J 2.2 Hz), 4.04 (t, 1H, J=6.0Hz), 3.83 (t, 2H, J=6.0 Hz), 2.28 (s, 3H), 2.01 (pentet, 2H, J=6.0 Hz).Mass spectrum (MALDI-TOF, gentisic acid matrix) calcd. for C₁₄H₁₅ClO₅S₂:385.0 (M+Na). Found: 385.1.

c)N-[3-[3-(5-Chlorothiophenyl-2-sulfonyloxy)-5-methylphenoxy]propoxy]phthalimide

Diethyl azodicarboxylate (115 μL, 0.68 mmol) was added dropwise over 8.5min to 3-[3-(5-chlorothiophenyl-2-sulfonyloxy)-5-methylphenoxy]propanol(207 mg, 0.57 mmol, prepared in the preceding step), triphenylphoshpine(180 mg, 0.68 mmol), and N-hydroxyphthalimide (93 mg, 0.57 mmol) inanhydrous tetrahydrofuran (5.1 mL) at 0° C. under a nitrogen atmosphere.The solution was stirred at 0° C. for additional 30 min. The reactionmixture was concentrated and the residue purified by flash columnchromatography (dichloromethane) to give the title compound (272 mg,94%) as a colorless resin. ¹H-NMR (300 MHz, CDCl₃) δ7.86-7.75 (m, 4H),7.42 (d, 11H, J=4.1 Hz), 6.96 (d, 1H, J=4.1 Hz), 6.69 (br s, 1H), 6.52(br s, 11H), 6.44 (br s, 1H), 4.39 (t, 2H, J=6.1 Hz), 4.16 (t, 2H, J=6.1Hz), 2.29 (s, 3H), 2.21 (pentet, 2H, J=6.1 Hz). Mass spectrum(MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₂₂H₁₈ClN₇S₂: 530.0 (M+Na). Found: 529.5.

d) 3-[3-(5-Chlorothiophenyl-2-sulfonyloxy)-5-methylphenoxy]propoxyamine

Sodium borohydride (85 mg, 2.2 mmol) was added to a solution ofN-[3-[3-(5-chlorothiophenyl-2-sulfonyloxy)-5-methylphenoxy]propoxy]phthalimide(227 mg, 0.45 mmol, prepared in the preceding step) in 2-propanol (23.3mL), tetrahydrofuran (5.8 mL), and water (3.9 mL). Hydrogen gas wasevolved. The mixture was stirred overnight at ambient temperature. Thereaction mixture was carefully acidified with aqueous HCl (6.6 mL, 2N),and the solution was stirred at 50° C. for 2 h. The solution was cooledto 0° C. and neutralized (pH 7) with 2N NaOH. Organic solvent wasremoved by rotary evaporation, and the resulting mixture was extractedwith ethyl acetate (2×15 mL). The combined organic extracts were washedwith brine (15 mL), dried over Na₂SO₄, filtered, and evaporated. Theresidue was purified by flash column chromatography (25% ethyl acetatein hexane) to give the title compound (141 mg, 84%) as a colorless oil.¹H-NMR (300 MHz, CDCl₃) δ7.40 (d, 1H, J=4.0 Hz), 6.95 (d, 1H, J=4.0 Hz),6.65 (br s, 1H), 6.48 (br s, 1H), 6.43 (t, 1H, J=2.2 Hz), 5.39 (br s,2H), 3.96 (t, 2H, J=6.3 Hz), 3.81 (t, 2H, J=6.1 Hz), 2.28 (s, 3H), 2.03(pentet, 2H, J=6.2 Hz). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₄H₁₆ClNO₅S₂: 378.0(M+H), 400.0 (M+Na). Found: 377.6, 399.5.

e)3-[3-(5-Chlorothiophenyl-2-sulfonyloxy)-5-methylphenoxy]propoxyguanidinehydrochloride

A solution of3-[3-(5-chlorothiophenyl-2-sulfonyloxy)-5-methylphenoxy]propoxyamine(129 mg, 0.34 mmol, prepared in the preceding step) and1H-pyrazole-1-carboxamidine hydrochloride (103 mg, 0.70 mmol) inanhydrous N,N-dimethylformamide (1.5 mL) was stirred at ambienttemperature overnight. Additional 1H-pyrazole-1-carboxamidinehydrochloride (103 mg, 0.70 mmol) was added, and the reaction was againstirred at ambient temperature overnight. N,N-Dimethylformamide wasremoved in vacuo, and the residue was treated with acetonitrile (3 mL).The mixture was filtered to remove excess 1H-pyrazole-1-carboxamidinehydrochloride, and the filtrate was concentrated. The residual oil waspartitioned between diethyl ether (15 mL) and water (10 mL). The aqueouslayer was washed with diethyl ether (2×15 mL), basified (pH 8) with 2NNaOH, and extracted with ethyl acetate (2×20 mL). The ethyl acetateextracts were washed with pH 7 buffer (2×25 mL) and brine (25 mL), driedover Na₂SO₄, filtered, and evaporated to give the free base of the titlecompound (129 mg, 90%) as a colorless oil.

The hydrochloride salt of the title compound was made by adding asolution of the free base,3-[3-(5-chlorothiophenyl-2-sulfonyloxy)-5-methylphenoxy]propoxyguanidine,(114 mg, 0.27 mmol, prepared above) in a minimum volume oftetrahydrofuran to anhydrous diethyl ether (100 mL) containing HCl inethanol (0.75 mL, 1.1 M, 0.82 mmol). Solvent was removed in vacuo togive 130 mg of the title compound as a pale yellow oil. ¹H-NMR (300 MHz,DMSO-d₆) δ7.76 (d, 2H, J=4.2 Hz), 7.41 (d, 2H, J=4.2 Hz), 6.80 (br s,1H), 6.55 (br s, 1H), 6.49 (t, 1H, J=2.2 Hz), 4.02 (t, 2H, J=6.3 Hz),3.92 (t, 2H, J=6.3 Hz), 2.26 (s, 3H), 2.03 (pentet, 2H, J=6.3 Hz). Massspectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₁₅H₁₈ClN₃O₅S₂: 420.0 (M+H). Found: 419.9.

EXAMPLE 63-[3-(2-Cyanophenylsulfonyloxy)-5-methylphenoxy]propoxyguanidinehydrochloride

a) 3-(2-Cyanophenylsulfonyloxy)-5-methylphenol

Orcinol monohydrate (1.42 g, 10.0 mmol) and 2-cyanobenzenesulfonylchloride 2.02 g, 10.0 mmol) were mixed in saturated NaHCO₃ (30 mL) anddiethyl ether 30 mL). The biphasic mixture was stirred vigorously atroom temperature overnight. The reaction mixture was diluted with water(50 mL) and extracted into ethyl acetate (3×50 mL). The organic phasewas washed with brine (2×50 mL) and dried over Na₂SO₄. After removingthe solvent in vacuo, the residue was purified by flash columnchromatography (dichloromethane to 5% ethyl acetate in dichloromethane)to give the title compound as a white solid (1.65 g, 57%). ¹H-NMR (300MHz, CDCl₃) δ8.07 (m, 1H), 7.94 (m, 1H), 7.75-7.80 (m, 2H), 6.57 (s,1H), 6.53 (s, 1H), 6.49 (s, 1H), 5,69 (br s, 1H), 2.22 (s, 3H).

b) 3-[3-(2-Cyanophenylsulfonyloxy)-5-methylphenoxy]propanol

To a solution of 3-(2-cyanophenylsulfonyloxy)-5-methylphenol (580 mg,2.0 mmol), as prepared in preceding step, tri-n-butylphosphine (607 mg,3.0 mmol), and 1,3-propanediol (760 mg, 10 mmol) in tetrahydrofuran (20mL) was added 1,1′-(azodicarbonyl)dipiperidine (757 mg, 3.0 mmol). Themixture was stirred at room temperature overnight. Hexane (30 mL) wasadded to the mixture, and the precipitates were removed by filtration.The filtrate was evaporated in vacuo, and the residue was purified byflash column chromatography (10% ethyl acetate in dichloromethane) togive the title compound as a colorless oil (560 mg, 80%). ¹H-NMR (300MHz, CDCl₃) δ8.11 (m, 1H), 7.94 (m, 1H), 7.77-7.82 (m, 2H), 6.65 (s, 1H,6.59 (s, 1H), 6.57 (s, 1H), 4.05 (t, J=6.0 Hz, 2H), 3.82 (t, J=6.0 Hz,2H), 2.26 (s, 3H), 2.00 (m, 2H), 1.76 (br s, 1H).

c)N-[3-[3-(2-Cyanophenylsulfonyloxy)-5-methylphenoxy]propoxy]phthalimide

To a solution of3-[3-(2-cyanophenylsulfonyloxy)-5-methylphenoxy]propanol (1.04 g, 3.0mmol), as prepared in the preceding step, triphenylphosphine (1.05 g,4.0 mmol), and N-hydroxyphthalimide (490 mg, 3.0 mmol) at 0° C. intetrahydrofuran (20 mL) was added diethyl azodicarboxylate (700 mg, 4.0mmol). The reaction mixture was stirred overnight. Water (50 mL) wasadded, the reaction mixture was extracted into ethyl acetate (3×50 mL).The ethyl acetate solution was washed with brine (2×50 mL) and driedover Na₂SO₄. After removing the solvent, the residue was purified byflash column chromatography (2:1 dichloromethane/hexane todichloromethane) to give the title compound as a colorless foam (1.12 g,76%). ¹H-NMR (300 MHz, CDCl₃) δ8.09 (m, 1H), 7.97 (m, 1H), 7.84 (m, 2H),7.78 (m, 4H), 6.67 (s, 1H), 6.60 (s, 1H), 6.50 (s, 1H), 4.37 (t, J=6.1Hz, 2H), 4.13 (t, J=6.1 Hz, 2H), 2.27 (s, 3H), 2.19 (m, 2H).

d) 3-[3-(2-Cyanophenylsulfonyloxy)-5-methylphenoxy]propoxyamine

To a solution ofN-[3-[3-(2-cyanophenylsulfonyloxy)-5-methylphenoxy]propoxy]phthalimide(600 mg, 1.2 mmol), as prepared in the preceding step, in 40 mL ofethanol/tetrahydrofuran/water (2:1:1) was added sodium borohydride (230mg, 6.0 mmol). The reaction mixture was stirred at ambient temperatureovernight. The mixture was acidified (pH 1-2) and heated to 50° C. for 2hours. After cooling to room temperature, the solution was adjusted topH 8-9 with 2N NaOH. The mixture was extracted into ethyl acetate (3×50mL), and the organic phase was washed with brine (50 mL) and dried overNa₂SO₄. After removing the solvent, the residue was purified by flashcolumn chromatography (dichloromethane to 2% methanol indichloromethane) to give the title compound as a colorless oil (370 mg,85%). ¹H-NMR (300 MHz, CDCl₃) δ8.06 (m, 1H), 7.93 (m, 1H), 7.76 (m, 2H),6.61 (s, 1H), 6.53 (s, 2H), 5.36 (br s, 2H), 3.94 (t, J=6.3 Hz, 2H),3.78 (t, J=6.2 Hz, 2H), 2.23 (s, 3H), 1.99 (m, 2H).

e) 3-[3-(2-Cyanophenylsulfonyloxy)-5-methylphenoxy]propoxyguanidinehydrochloride

To a solution of3-[3-(2-cyanophenylsulfonyloxy)-5-methylphenoxy]propoxyamine (362 mg,1.0 mmol), as prepared in the preceding step, in N,N-dimethylformamide(10 mL) was added 1H-pyrazole-carboxamidine hydrochloride (590 mg, 4.0mmol). The reaction mixture was stirred at ambient temperature for twodays. N,N-Dimethylformamide was removed under high vacuum. Acetonitrile(10 mL) was added, the solid was removed by filtration, the filtrate wasconcentrated in vacuo, and the residue was dried under high vacuum. Theresidue was partitioned between water (30 mL plus 2 mL brine) anddiethyl ether (20 mL). The water solution was extracted with diethylether (20 mL), and the combined diethyl ether extracts were extractedwith acidic water (pH 5). The combined water solutions were adjusted topH 8-9 by using 2N NaOH and extracted with ethyl acetate (3×50 mL). Theethyl acetate solution was washed with pH 7 buffer solution (2×30 mL)and brine (30 mL) and dried over Na₂SO₄. After removing the solvent,0.6N HCl methanol (10 mL) was added, and the solution was concentratedto give the title compound as a colorless oil (340 mg, 77%). ¹H-NMR (300MHz, DMSO-d₆) δ8.30 (d, J=7.5 Hz, 1H), 8.09 (t, J=7.5 Hz, 1H), 8.04 (m,2H), 7.72 (br s, 5H), 6.79 (s, 1H), 6.49 (s, 1H), 6.47 (s, 1H), 3.99 (t,J=6.2 Hz, 2H), 3.90 (t, J=6.3 Hz, 2H), 2.22 (s, 3H), 2.01 (m, 2H). Massspectrum (MALDI-TOF, (α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₁₈H₂₀N₄O₅S: 405.1 (M+H), 427.1 (M+Na). Found: 405.1, 427.0.

EXAMPLE 73-[3-(5-Isoquinolinylsulfonyloxy)-5-methylphenoxy]propoxyguanidinehydrochloride

a) 5-Isoquinolinesulfonyl chloride

A mixture of 5-isoquinolinesulfonic acid (4.18 g, 20 mmol), andphosphorus pentachloride (6.24 g, 30 mmol) in phosphorus oxychloride (20mL) was heated at 120 ° C. for two days. The reaction mixture was cooledto room temperature and diluted with dry chloroform (60 mL). The whiteprecipitate was collected, washed with dry chloroform, and dried underhigh vacuum to give the title compound as a white solid (4.40 g, 83%)which was used for next step without further purification. ¹H-NMR (300MHz, CDCl₃)δ9.95 (s, 1H), 9.16 (d, J=6.8 Hz, 1H), 8.74 (d, J=6.8 Hz,1H), 8.52 (t, J=7.0 Hz, 2H), 7.99 (t, J=7.3 Hz, 1H).

b) 3-(5-Isoquinolinylsulfonyloxy)-5-methylphenol

Orcinol monohydrate (1.42 g, 10.0 mmol) and 5-isoquinolinesulfonylchloride (2.64 g, 10.0 mmol), as prepared in the preceding step, weremixed in saturated NaHCO₃ (30 mL) and diethyl ether (30 mL). Thebiphasic mixture was stirred vigorously at room temperature overnight.The reaction mixture was diluted with water (50 mL) and extracted intoethyl acetate (3×50 mL). The organic phase was washed with brine (2×50mL) and dried over Na₂SO₄. After removing the solvent in vacuo, theresidue was triturated with ether/hexane to give the title compound as apale yellow solid (1.15 g, 37%). ¹H-NMR (300 MHz, CDCl₃) δ9.67 (s, 1H),9.60 (s, 1H), 8.86 (d, J=6.1 Hz, 1H), 8.63 (d, J=8.2 Hz, 1H), 8.37 (t,J=6.1 Hz, 2H), 7.86 (t, J=7.8 Hz, 1H), 6.46 (s, 1H), 6.23 (s, 1H), 5.97(3, 1H), 2.08 (s, 3H).

c) 3-[3-(5-Isoquinolinylsulfonyloxy)-5-methylphenoxy]propanol

To a solution of 3-(5-isoquinolinylsulfonyloxy)-5-methylphenol (630 mg,2.0 mmol), as prepared in the preceding step, tri-n-butylphosphine (607mg, 3.0 mmol), and 1,3-propanediol (760 mg, 10 mmol) in tetrahydrofuran(20 mL) was added 1,1′-(azodicarbonyl)dipiperidine (757 mg, 3.0 mmol).The mixture was stirred at room temperature overnight. Hexane (30 mL)was added to the mixture, and the precipitates were removed byfiltration. The filtrate was evaporated in vacuo, the residue waspurified by flash column chromatography (4:1 ethyl acetate/CH₂Cl₂) togive the title compound as a colorless oil (620 mg, 82%). ¹H-NMR (300MHz, CDCl₃) δ9.41 (s, 1H), 8.80 (d, J=6.1 Hz, 1H), 8.54 (d, J=6.1 Hz,1H), 8.33 (d, J=7.2 Hz, 1H), 8.29 (d, J=7.6 Hz, 1H), 7.67 (t, J=7.7 Hz,1H), 6.56 (s, 1H), 6.29 (s, 1H), 6.24 (s, 1H), 3.89 (t, J=6.1 Hz, 2H),3.75 (t, J=6.0 Hz, 2H), 2.16 (s, 3H), 2.05 (m, 2H), 1.90 (br s, 1H).

d)N-[3-[3-(5-Isoquinolinylsulfonyloxy)-5-methylphenoxy]propoxy]phthalimide

To a solution of3-[3-(5-isoquinolinylsulfonyloxy)-5-methylphenoxy]propanol (560 mg, 1.5mmol), as prepared in the preceding step, triphenylphosphine (520 mg,2.0 mmol), and N-hydroxyphthalimide (245 mg, 1.5 mmol) intetrahydrofuran (15 mL) at 0° C. was added diethyl azodicarboxylate (350mg, 2.0 mmol). The reaction mixture was stirred at room temperatureovernight. Water (50 mL) was added, and the reaction mixture wasextracted into ethyl acetate (3×50 mL). The ethyl acetate solution waswashed with brine (2×50 mL) and dried over Na₂SO₄. After removing thesolvent, the residue was purified by flash column chromatography (4:1dichloromethane/ethyl acetate) to give the title compound as a colorlessfoam (580 mg, 75%). ¹H-NMR (300 MHz, CDCl₃) δ9.42 (s, 1H), 8.81 (d,J=6.1 Hz, 1H), 8.56 (d, J=6.1 Hz, 1H), 8.34 (d, J=7.1 Hz, 1H), 8.31 (d,J=7.2 Hz, 1H), 7.84 (m, 2H), 7.77 (m, 2H), 7.68 (t, J=7.7 Hz, 1H), 6.59(s, 1H), 6.33 (s, 1H), 6.21 (s, 1H), 4.31 (t, J=6.1 Hz, 2H), 4.00 (t,J=6.1 Hz, 2H), 2.17 (s, 3H), 2.11 (m, 2H).

e) 3-[3-(5-Isoquinolinylsulfonyloxy)-5-methylphenoxy]propoxyamine

To a solution ofN-[3-[3-(5-isoquinolinylsulfonyloxy)-5-methylphenoxy]propoxy]phthalimide(570 mg, 1.1 mmol), as prepared in the preceding step, in ethanol (20mL), tetrahydrofuran (10 mL), and water (10 mL) was added sodiumborohydride (230 mg, 6.0 mmol). The reaction mixture was stirred atambient temperature overnight. The mixture was acidified (pH 1-2) with 2N HCl and heated at 50° C. for 2 hours. After cooling to roomtemperature, 2 N NaOH was added to adjust the pH to 8-9. The mixture wasextracted with ethyl acetate (3×50 mL). The combined organic extractswere washed with brine (50 mL) and dried over Na₂SO₄. After removing thesolvent, the residue was purified by flash column chromatography (ethylacetate) to give the title compound as a colorless oil (110 mg, 26%).¹H-NMR (300 MHz, CDCl₃) δ9.42 (s, 1H), 8.81 (d, J=6.1 Hz, 1H), 8.54 (d,J=6.1 Hz, 1H), 8.33 (m, 2H), 7.67 (t, J=7.8 Hz, 1H), 6.55 (s, 1H), 6.28(s, 1H), 6.23 (s, 1H), 3.81 (t, J=6.3 Hz, 2H), 3.74 (t, J=6.1 Hz, 2H),2.15 (s, 3H), 1.94 (m, 2H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₉H₂₀N₂O₅S: 389.1(M+H), 411.1 (M+Na). Found: 389.3, 411.1.

f) 3-[3-(5-Isoquinolinylsulfonyloxy)-5-methylphenoxy]propoxyguanidinehydrochloride

To a solution of3-[3-(5-isoquinolinylsulfonyloxy)-5-methylphenoxy]propoxyamine (100 mg,0.25 mmol), as prepared in the preceding step, in N,N-dimethylformamide(4 mL) was added 1H-pyrazole-carboxamidine hydrochloride (150 mg, 1.0mmol). The reaction mixture was stirred at ambient temperature for twodays. N,N-Dimethylformamide was removed under high vacuum. Acetonitrile(5 mL) was added and the solid was removed by filtration. The filtratewas concentrated in vacuo and the residue was dried under high vacuum.The residue was partitioned between water (20 mL plus 2 mL brine) anddiethyl ether (10 mL). The water solution was extracted with diethylether (10 mL). The combined diethyl ether extracts were extracted withpH 5 water. The combined water solution was basified (pH 8-9) by using 2N NaOH and extracted with ethyl acetate (3×30 mL). The ethyl acetatesolution was washed with pH 7 buffer solution (2×20 mL) and brine (20mL) then dried over Na₂SO₄. After removing the solvent, 0.6 N HClmethanol (3 mL) was added, and the solution was concentrated to give thetitle compound as colorless foam (95 mg, 81%). ¹H-NMR (300 MHz, DMSO-d₆)δ11.16 (br s, 1H), 9.75 (s, 1H), 8.89 (d, J=6.3 Hz, 1H), 8.73 (d, J=8.3Hz, 1H), 8.46 (m, 4H), 7.93 (t, J=7.9 Hz, 1H), 7.72 (br s, 4H), 6.71 (s,1H), 6.33 (s, 1H), 6.27 (s, 1H), 3.88 (m, 4H), 2.13 (s, 3H), 1.94 (m,2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix)calcd. for C₂₀H₂₂N₄O₅S: 431.1 (M+H), 453.1 (M+Na). Found: 431.2, 453.3.

EXAMPLE 83-[5-Methyl-3-[2-(methylsulfonyl)phenylsulfonyloxy]phenoxy]propoxyguanidinehydrochloride

a) 5-Methyl-3-[2-(methylsulfonyl)phenylsulfonyloxy]phenol

A mixture of orcinol monohydrate (1.68 g, 12 mmol) and2-methylsulfonylbenzenesulfonyl chloride (3.0 g, 11.8 mmol) in saturatedNaHCO₃ (25 mL) and dichloromethane (25 mL) was stirred vigorously atroom temperature for one week. The reaction mixture was diluted with 50mL of water and extracted into dichloromethane (3×50 mL). The organicphase was washed with brine (2×50 mL) and dried over Na₂SO₄. Afterremoving the solvent in vacuo, the residue was treated withdichloromethane and ether to initiate crystallization. The mixture wasfiltered to provide 1.05 g (26% yield) of a white solid. ¹H-NMR (300MHz, CDCl₃) δ2.22 (s, 3H), 3.45 (s, 3H), 5.20 (s, 1H), 6.51 (t, 1H),6.54 (s, H), 6.61 (s, 1H), 7.74 (td, 1H, J=7.7, 1.4 Hz), 7.87 (td, 1H,J=7.7, 1.3 Hz), 8.12 (dd, 1H, J=7.8, 0.7 Hz), and 8.44 (dd, 1H, J=7.8,0.5 Hz).

b) 3-[5-Methyl-3-[2-(methylsulfonyl)phenylsulfonyloxy]phenoxy]propanol

Diethyl azodicarboxylate (0.46 mL, 2.9 mmol) was added slowly to asolution of 1.0 g (2.9 mmol) of5-methyl-3-[2-(methylsulfonyl)phenylsulfonyloxy]phenol, as prepared inthe preceding step, 0.21 mL (2.9 mmol) of 1,3-propanediol, and 760 mg(2.9 mmol) of triphenylphosphine in tetrahydrofuran (25 mL). Thereaction mixture was stirred at ambient temperature overnight. Thereaction mixture was evaporated to dryness. The residue was trituratedwith hexane under sonication and decanted (4 times). The residue wasdissolved in dichloromethane and diluted with hexane to produce acrystalline material, which was discarded. The filtrate was diluted withhexane to give an oil and the solvent was decanted. The oil wasdissolved in a minimum of methanol and diluted with water to initiatecrystallization. The solid was collected by filtration to afford thetitle compound 1.16 g (quantitative yield). ¹H-NMR (300 MHz, CDCl₃)δ8.45 (dd, 1H, J=7.8, 1.3 Hz), 8.12 (dd, 1H, J=7.8, 1.2 Hz), 7.88 (td,1H, J=7.7, 1.3 Hz), 7.74 (td, 1H, J=7.7, 1.3 Hz), 6.61-6.56 (m, 3H),4.00 (t, 2H, J=6Hz), 3.81 (t, 3H, J=5.9 Hz), 3.45 (s, 3H), 2.24 (s, 3H),and 1.97 (pentet, 2H, J=6.2 Hz). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₇H₂₀O₇S₂: 423.1(M+Na). Found: 423.1.

c)N-[3-[5-Methyl-3-[2-(methylsulfonyl)phenylsulfonyloxy]phenoxy]propoxy]phthalimide

The diethyl azodicarboxylate (3.5 mL, 0.022 mol) was added dropwise to asolution of3-[5-methyl-3-[2-(methylsulfonyl)phenylsulfonyloxy]phenoxy]propanol (7.4g, 0.018 mol), as prepared in the preceding step, triphenylphosphine(5.82 g, 0.018 mol), and N-hydroxyphthalimide (3.11 g, 0.018 mol) inanhydrous tetrahydrofuran (120 mL). The solution was allowed to stir atambient temperature over a weekend. The tetrahydrofuran was evaporated.The residue was dissolved in acetonitrile (minimum) and diluted withhexane to produce a crystalline product which was collected byfiltration and discarded. The filtrate was evaporated to dryness andpurified by silica gel chromatography using dichloromethane as anelution solvent. The appropriate fractions were combined, evaporated todryness, and placed under high vacuum to give 7.3 g (74% yield) of acolorless foam. ¹H-NMR (300 MHz, CDCl₃) δ8.45 (dd, 1H, J=7.8, 1.3 Hz),8.12 (dd, 1H, J=7.8, 1.2 Hz), 7.82-7.91 (m, 3H), 7.73-7.79 (m, 3H),6.61-6.63 (m, 2H), 6.55 (t, 1H, J=2.1 Hz), 4.36 (t, 2H, J=6.2 Hz), 4.10(m, 2H), 3.45 (s, 3H), 2.24 (s, 3H), 2.13-2.23 (pentet, 2H, J=6.2 Hz).Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd.for C₂₅H₂₃NO₉S₂: 568.1 (M+Na). Found: 568.0.

d)3-[5-Methyl-3-[2-(methylsulfonyl)phenylsulfonyloxy]phenoxypropoxyamine

A solution ofN-[3-[5-methyl-3-[2-(methylsulfonyl)phenylsulfonyloxy]phenoxy]propoxy]phthalimide(7.22 g, 0.013 mol), as prepared in the preceding step, inisopropanol:tetrahydrofuran:water (5:1:1; 700 mL) was treated withsodium borohydride (2.5 g, 0.066 mol). The reaction mixture was allowedto stir at ambient temperature overnight. The reaction mixture wasquenched with 2N hydrochloric acid and the mixture was warmed at 50° C.for 2.5 hours. The reaction mixture was cooled in an ice:water bath andadjusted to pH 8.0 with 2N sodium hydroxide. The isopropanol wasevaporated on a rotary evaporator and the residual aqueous solution wasextracted with ethyl acetate (3×75 mL). The combined ethyl acetateextracts were washed with brine, dried over anhydrous sodium sulfate,and evaporated to dryness. The material was purified by silica gelchromatography by elution with 60% ethyl acetate/hexane, followed by 75%ethyl acetate/hexane. The appropriate fractions were combined andevaporated to 2.8 g (52% yield) of a white solid. ¹H-NMR (300 MHz,CDCl₃) δ8.45 (dd, J=7.9, 1.2 Hz, 1H), 8.11 (dd, J=7.8, 1.3 Hz, 1H), 7.87(td, J=7.7, 1.3 Hz, 1H), 7.74 (td, J=7.8, 1.3 Hz, 1H), 6.56-6.60 (m,3H), 5.39 (m, 2H), 3.92 (t, J=6.3 Hz, 2H), 3.79 (t, J=6.1 Hz, 2H), 3.45(s, 3H), 2.23 (s, 3H), and 1.99 (pentet, J=6.2 Hz, 2H). Mass spectrum(MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₁₇H₂₁NO₇S₂: 438.1 (M+Na). Found: 438.2.

e)3-[5-Methyl-3-[2-(methylsulfonyl)phenylsulfonyloxy]phenoxy]propoxyguanidinehydrochloride

A solution of3-[5-methyl-3-[2-(methylsulfonyl)phenylsulfonyloxy]phenoxy]propoxyamine(2.75 g, 0.0066 mol), as prepared in the preceding step, in anhydrousN,N-dimethylformamide (100 mL) was treated with1H-pyrazole-1-carboxamidine hydrochloride (2.93 g, 0.02 mol). Thereaction mixture was allowed to stir overnight at ambient temperature.The reaction mixture was evaporated to dryness under high vacuum. Theresidue was treated with acetonitrile and the resulting crystallinematerial was collected by filtration and discarded. The filtrate wasevaporated to dryness and applied to a silica gel column. The column waseluted with 5% methanol in acetonitrile, which resulted in mixed productfractions. These fractions were combined and evaporated to dryness. Theresidue was dissolved in water and the solution was adjusted to pH 3-4with methanolic HCl. This solution was washed with ether and ethylacetate. The aqueous solution was treated with solid sodium chloride andextracted with ethyl acetate and dichloromethane. Both the ethyl acetateand the dichloromethane extracts were separately washed with brine anddried (Na₂SO₄). The organic extracts were combined and evaporated todryness. The residue was triturated with both hexane and ether undersonication and decanted. The residue was placed under high vacuum withsonication for 2 h to give 2.67 g (82% yield) of a white powder. ¹H-NMR(300 MHz, CDCl₃) δ8.42 (dd, J=7.8, 1.3 Hz, 1H), 8.10 (dd, J=7.8, 1.3 Hz,1H), 7.90 (td, J=7.7, 1.3 Hz, 1H), 7.77 (td, J=7.7, 1.3 Hz, 1H), 7.27(broad), 6.57 (m, 2H), 6.52 (br t, 1H), 4.04 (t, J=6.1 Hz, 2H), 3.94 (t,J=5.6 Hz, 2H), 3.43 (s, 3H), 2.21 (s, 3H), and 2.06 (pentet, J=5.6 Hz,2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix)calcd. for C₁₈H₂₃N₃O₇S₂: 458.1 (M+H). Found: 457.9. HPLC (C18, 5μ,4.6×100 mm, Gradient: 5→100% B in 15 min; A=0.1% TFA/H₂O; B=0.1%TFA/CH₃CN, 20 μL inj, 15 min run time, Det: 215 nm, FR:1 mL/min) 98%@8.74 min.

EXAMPLE 93-[-5-Methyl-3-(1,2,3,4-tetrahydroquinolinyl-8-sulfonyloxy)phenoxy]propoxyguanidineacetate

A solution of3-[5-methyl-3-(quinolinyl-8-sulfonyloxy)phenoxy]propoxyguanidinehydrochloride (0.317 g, 0.68 mmol), as prepared in Example 3, inmethanol (32 mL) was evacuated, flushed with nitrogen, then treated with10% palladium on carbon (115 mg). The reaction was then placed under ahydrogen-filled balloon. After 8 hours, a 52 mg-portion of 10% palladiumon carbon was added and the reaction was again placed under ahydrogen-filled balloon. After stirring overnight, the reaction mixturewas filtered through Celite and the filtrate was evaporated to dryness.The residue was triturated with hexane twice. The residue was taken upin a minimum amount of acetonitrile, filtered through a PTFE filter(0.45μ), and evaporated to dryness. The residue was purified on a WatersSep-Pak silica gel column (5 g silica) by elution with a mixture of 40%dichloromethane:methanol:acetic acid (400/100/10) in dichloromethane.The appropriate fractions were combined and evaporated to dryness. Theresidue was triturated with hexane twice and then placed under highvacuum. The residue was treated with 50% aqueous acetonitrile andlyophilized overnight to give the title compound as a hydroscopic solid(0.248 g, 74% yield). ¹H-NMR (300 MHz, CDCl₃) δ7.28 (d, J=8.0 Hz, 1H),7.08 (d, J=7.1 Hz, 1H), 6.54 (s, 1H), 6.36-6.45 (m, 3H), 6.01 (broad s,1H), 4.04 (m, 2H), 3.91 (m, 2H), 3.67 (m, 2H), 2.75(t, J=6.1 Hz, 2H),2.18 (s, 3H), 2.03 (m, 2H), 1.87 (pentet, J=5.4 Hz, 2H). Mass spectrum(MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₂₀H₂₆N₄O₅S: 435.2 (M+H). Found: 434.9. HPLC (C18, 5μ, 4.6×100 mm,Gradient: 5→100% B in 15 min; A=0.1% TFA/H₂O; B=0.1% TFA/CH₃CN, 20 μLinj, 15 min run time, Det: 215 nm, FR: 1 mL/min) 98.8% @10.0 min.

EXAMPLE 103-[5-Hydroxymethyl-3-(quinolinyl-8-sulfonyloxy)phenoxy]propoxyguanidineacetic acid salt

a) 5-Methoxycarbonyl-3-(quinolinyl-8-sulfonyloxy)phenol

A mixture of methyl 1,3-dihydroxybenzoate (2.56 g, 0.015 mol) and8-quinolinesulfonyl chloride (3.46 g, 0.015 mol) in dichloromethane (100mL) and saturated sodium bicarbonate (100 mL) was stirred at roomtemperature for 5 days. The reaction mixture was diluted with water anddichloromethane. The dichloromethane was separated and the aqueous layerwas extracted with dichloromethane (2×25 mL). The dichloromethaneextracts were combined, washed with water and brine, dried over sodiumsulfate and evaporated to dryness. The residue was treated with methanoland filtered to remove insoluble material. The filtrate was evaporatedto dryness to give the title compound as a pale yellow foam (4.34 g, 80%yield) which was used without further purification.

b) 3-[5-Methoxycarbonyl-3-(quinolinyl-8-sulfonyloxy)phenoxy]propanol

A mixture of 5-methoxycarbonyl-3-(quinolinyl-8-sulfonyloxy)phenol (4.34g, 0.012 mol), as prepared in the preceding step, 3-bromo-1-propanol,and cesium carbonate (3.91 g, 0.012 mol) in acetonitrile (40 mL) waswarmed at 50° C. overnight. The reaction mixture was diluted with ethylacetate (2×25 mL). The ethyl acetate layers were combined, washed withbrine, dried, and evaporated to dryness. The residue was purified on asilica gel column (80 g) by elution with 10-20% ethyl acetate indichloromethane. The appropriate fractions were collected, evaporated todryness, and placed under high vacuum to give the title compound as awhite solid (2.83 g, 57% yield). ¹H-NMR (300 MHz, CDCl₃) δ9.25 (dd, 1H,J=4.2, 1.8 Hz), 8.43 (dd, 1H, J=7.4, 1.4 Hz), 8.31 (dd, 1H, J=8.4, 1.7Hz), 8.16 (dd, 1H, J=8.2, 1.4 Hz), 7.60-7.66 (m, 2H), 7.41 (m, 1H), 7.30(m, 1H), 6.91 (t, 1H, J=2.3 Hz), 4.03 (t, 2H, J=6.0 Hz), 3.83 (s, 3H),3.80 (t, 2H, J=6.0 Hz), 1.98 (pentet, 2H, J=6.0 Hz). Mass spectrum(MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₂₀H₁₉NO₇S: 418.1 (M+H). Found:417.9.

c)N-[3-[5-Methoxycarbonyl-3-(quinolinyl-8-sulfonyloxy)phenoxy]propoxy]phthalimide

A solution of3-[5-methoxycarbonyl-3-(quinolinyl-8-sulfonyloxy)phenoxy]propanol (2.83g, 0.0068 mol), as prepared in the preceding step, triphenylphosphine(2.1 g, 0.008 mol), and N-hydroxyphthalimide (1.11 g, 0.0068 mol) inanhydrous tetrahydrofuran (50 mL) was treated with diethylazodicarboxylate (1.26 mL, 0.008 mol) dropwise. The reaction mixture wasallowed to stir at ambient temperature overnight. The tetrahydrofuranwas evaporated and the residue was treated with acetonitrile/hexane toproduce a crystalline crop which was removed by filtration anddiscarded. The filtrate produced a granular crystalline material whichwas collected by filtration and discarded. The filtrate was evaporatedto dryness and the residue was treated with ethyl acetate/hexane toproduce the title compound as a crystalline material in two crops (3.53g, 92% yield). ¹H-NMR (300 MHz, CDCl₃) indicated 88% title compound and12% triphenylphosphine oxide: δ9.28 (dd, 1H, J=4.2, 1.7 Hz), 8.43 (dd,1H, J=7.4, 1.4 Hz), 8.31 (dd, 1H, J=8.4, 1.8 Hz), 8.16 (dd, 1H, J=8.2,1.4 Hz), 7.75-7.88 (m, 4H), 7.60-7.71 (m, 2H), 7.43 (m, 1H), 7.33 (m,1H), 6.88 (t, 1H, J=2.3 Hz), 4.35 (t, 2H, J=6.1 Hz), 4.13 (t, 2H,J=6.1), 3.84 (s, 3H), 2.18 (pentet, 2H, J=6.1 Hz). Mass spectrum(MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₂₈H₂₂N₂O₉S: 563.1 (M+H). Found: 563.1.

d) 3-[5-Hydroxymethyl-3-(quinolinyl-8-sulfonyloxy)phenoxy]propoxyamine

A suspension ofN-[3-[5-methoxycarbonyl-3-(quinolinyl-8-sulfonyloxy)phenoxy]propoxy]phthalimide(3.52 g, 0.0063 mol), as prepared in the preceding step, inethanol/tetrahydrofuran/water (48:48:24 mL each) was treated with sodiumborohydride (1.2 g) and the reaction was stirred at ambient temperatureovernight. The reaction mixture was quenched with 2N HCl and warmed at50° C. for 2.5 h while maintaining a pH of 2.0. The solvents wereevaporated and the concentrate was cooled in an ice bath, adjusted topH=10 with 2N NaOH, and extracted with ethyl acetate (4×25 mL). Theethyl acetate extracts were combined, washed with brine, dried, andevaporated. The residue was dissolved in ethyl acetate and extractedwith 10% citric acid (3×25 mL). The citric acid extracts were combinedand washed with ethyl acetate (1×20 mL). The citric acid layer wasadjusted to pH=10 with 2N NaOH and extracted with ethyl acetate (3×25mL). The ethyl acetate extracts were combined, washed with brine, dried,and evaporated to dryness. The residue was placed under high vacuumovernight to give the title compound (1.2 g, 54% yield). Mass spectrum(MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forCl₁₉H₂₀N₂O₆S: 405.1 (M+H). Found: 405.0, also 278.9 fortriphenylphosphine oxide.

e)3-[5-Hydroxymethyl-3-(quinolinyl-8-sulfonyloxy)phenoxy]propoxyguanidineacetic acid salt

A solution of3-[5-hydroxymethyl-3-(quinolinyl-8-sulfonyloxy)phenoxy]propoxyamine (1.2g, 0.003 mol), as prepared in the preceding step, inN,N-dimethylformamide (25 mL) was treated with1H-pyrazole-1-carboxamidine hydrochloride (1,3 g, 0.009 mol) and thereaction mixture was stirred at ambient temperature overnight. TheN,N-dimethylformamide was evaporated under high vacuum. The residue wastriturated with hot acetonitrile and filtered. The filtrate wasevaporated to dryness. The residue was dissolved in water, acidified topH 3-4 with methanolic HCl, and washed with diethyl ether. The aqueouslayer was adjusted to pH 9-10 with 2N NaOH and extracted with ethylacetate (3×25 mL). The ethyl acetate extracts were combined, washed withpH 7 buffer and brine, dried, and evaporated to dryness. The residue wasredissolved in ethyl acetate and washed with pH 7 buffer and brine,dried, and evaporated. The residue was purified on a silica gel column(10 g) by elution with a 1:1 mixture of dichloromethane and a solutionof dichloromethane/methanol/acetic acid (400/100/10), followed by a 1:3mixture of the same composition. The appropriate fractions were combinedand evaporated. The residue was treated with acetonitrile and water andlyophilized overnight to give the title compound (0.8 g, 60% yield).¹H-NMR (300 MHz, CDCl₃/DMSO-d₆) δ9.25 (dd, 1H, J=4.2, 1.8 Hz), 8.38 (td,2H, J=7.5, 1.4 Hz), 8.20 (dd, 1H, J=8.3, 1.4 Hz), 7.62-7.68 (m, 2H),6.79 (s, 1H), 6.64 (s, 1H), 6.41 (t, 1H, J=2.3 Hz), 4.45 (s, 2H), 3.88(m, 4H), 1.93-2.02 (m, 5H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₂₀H₂₂N₄O₆S: 447.1(M+H). Found: 447.0. HPLC (C18, 5μ, 4.6×100 mm, Gradient: 5→100% B in 15min; A=0.1% TFA/H₂O; B=0.1% TFA/CH₃CN, 20 μL inj, 15 min run time, Det:215 nm, FR:1 mL/min) 95.8% @11.5 min.

EXAMPLE 11{1-[[5-Methyl-3-(2-methylsulfonylphenylsulfonyloxy)phenoxy]methyl]cyclopropylmethoxy}guanidinehydrochloride

a) 1,1-Dihydroxymethylcyclopropane

To a solution of BH₃.THF (1.0 M, 100 mL, 100 mmol) was added ethyl1,1-cyclopropanedicarboxylate (9.3 mL, 50 mmol) at room temperaturedropwise. The mixture was stirred at 50° C. overnight, quenched withmethanol (100 mL) carefully at 0° C. and stirred at room temperature for1 h. The reaction mixture was concentrated in vacuo. The residue wasco-evaporated with methanol several times (4×50 mL) to give the titlecompound as colorless oil (5.3 g) which was directly used in the nextstep without further purification.

b)[1-[5-Methyl-3-(2-methylsulfonylphenylsulfonyloxy)phenoxy]methyl]cyclopropylmethanol

To a solution of 3-(2-methylsulfonylphenylsulfonyloxy)-5-methylphenol(6.85 g, 20.0 mmol), as prepared in step a of Example 8,tri-N-butylphosphine (6.1 g, 30 mmol) and1,1-dihydroxylmethylcyclopropane (5.1 g, 50 mmol), as prepared in thepreceding step, in tetrahydrofuran (200 mL) was added1,1′-(azodicarbonyl)dipiperidine (7.6 g, 30 mmol). The mixture wasstirred at room temperature overnight, hexane (300 mL) was added to themixture and the precipitates were removed by filtration. The filtratewas evaporated in vacuo, the residue was purified by flash columnchromatography (1:1 to 2:1 ethyl acetate/hexane) and by crystallizationfrom ethyl acetate/hexane (1:5) to give the title compound as whitesolid (4.9 g, 57%). ¹H-NMR (300 MHz, CDCl₃) δ8.45 (d, J=7.8 Hz, 1H),8.13 (d, J=7.9 Hz, 1H), 7.88 (t, J=7.7 Hz, 1H), 7.75 (t, J=7.7 Hz, 1H),6.77 (br s, 3H), 3.82 (s, 2H), 3.59 (d, J=5.5 Hz, 2H), 3.45 (s, 3H),2.23 (s, 3H), 0.61 (s, 4H).

c)N-{1-[[5-Methyl-3-(2-methylsulfonylphenylsulfonyloxy)phenoxy]methyl]cyclopropylmethoxy}phthalimide

To a solution of[1-[5-methyl-3-(2-methylsulfonylphenylsulfonyloxy)phenoxy]methyl]cyclopropylmethanol(4.7 g, 11.0 mmol), as prepared in the preceding step,triphenylphosphine (3.4 g, 13.0 mmol), N-hydroxyphthalimide (2.1 g, 13.0mmol) in tetrahydrofuran (80 mL) was added diethyl azodicarboxylate (2.3g, 13.0 mmol) at 0° C. The reaction mixture was stirred at ambienttemperature overnight. The reaction mixture was concentrated in vacuoand ethyl acetate (100 mL) was added to the residue. The solid wascollected, washed with ethyl acetate and dried in high vacuum to givethe title compound as white solid (5.5 g, 87%). ¹H-NMR (300 MHz, CDCl₃)δ8.37 (d, J=7.8 Hz, 1H), 8.15 (d, J=7.8 Hz, 1H), 8.10 (t, J=7.7 Hz, 1H),7.97 (t, J=7.7 Hz, 1H), 7.86 (s, 4H), 6.77 (s, 1H), 6.54 (s, 1H), 6.51(s, 1H), 4.11 (s, 2H), 3.97 (s, 2H), 3.48 (s, 3H), 2.22 (s, 3H),0.61-0.66 (m, 4H).

d)N-{1-[[5-Methyl-3-(2-methylsulfonylphenylsulfonyloxy)phenoxy]methyl]cyclopropylmethoxy}amine

To a solution ofN-{1-[[5-methyl-3-(2-methylsulfonylphenylsulfonyloxy)phenoxy]methyl]cyclopropylmethoxy}phthalimide(5.4 g, 9.5 mmol), as prepared in the preceding step, in ethanol (100mL)/tetrahydrofuran (100 mL)/water (50 mL) was added sodium borohydride(1.15 g, 30.0 mmol). The reaction mixture was stirred at ambienttemperature overnight. 2N HCl was added to adjust the pH to 1-2, themixture was heated to 50° C. for 2 hours. The reaction mixture wasconcentrated to about 100 mL, water (50 mL) was added and the mixturewas neutralized to pH 8-9 with 2N NaOH. The mixture was extracted intoethyl acetate (3×100 mL) and the organic phase was washed with brine(2×100 mL) and then dried over Na₂SO₄. After removing the solvent, theresidue was purified by flash column chromatography (4:1 ethylacetate/hexane) to give the title compound as a white solid (3.6 g,86%). ¹H-NMR (300 MHz, CDCl₃) δ8.45 (d, J=7.8 Hz, 1H), 8.13 (d, J=7.8Hz, 1H), 7.88 (t, J=7.7 Hz, 1H), 7.74 (t, J=7.7 Hz, 1H), 6.61 (s, 1H),6.58 (s, 2H), 5.44 (br s, 2H),3.76 (s, 2H), 3,63 (s 2H), 3.45 (s, 3H),2.23 (s, 3H), 0.57-0.65 (m, 4H).

e){1-[[5-Methyl-3-(2-methylsulfonylphenylsulfonyloxy)phenoxy]methyl]cyclopropylmethoxy}guanidinehydrochloride

To a solution ofN-{1-[[5-methyl-3-(2-methylsulfonylphenylsulfonyloxy)phenoxy]methyl]cyclopropylmethoxy}amine(3.5 g, 8.0 mmol), as prepared in the preceding step, inN,N-dimethylformamide (30 mL) was added 1H-pyrazole-carboxamidinehydrochloride (3.7 g, 25.0 mmol). The reaction mixture was stirred atambient temperature overnight. N,N-Dimethylformamide was removed underhigh vacuum. Acetonitrile (50 mL) was added and the solid was removed byfiltration. The filtrate was concentrated in vacuo and the residue wasdried under high vacuum. The residue was partitioned between water (100mL plus 5 mL brine) and diethyl ether (50 mL). The water solution wasextracted with diethyl ether (50 mL). The combined diethyl ethersolution was extracted with pH 5 water (30 mL). The combined watersolution was adjusted to pH 8-9 by using 2N NaOH and extracted intoethyl acetate (3×100 mL). The ethyl acetate solution was washed with pH7 buffer solution (5×60 mL) and brine (50 mL) and dried over Na₂SO₄.After removing the solvent, 0.6N HCl methanol (50 mL) was added and thesolution was concentrated. The residual oil was crystallized frommethanol/ethyl acetate (1:50) to give the title compound as white solid(3.6 g, 86%). ¹H-NMR (300 MHz, DMSO-d₆) δ11.07 (br s, 1H), 8.37 (d,J=7.8 Hz, 1H), 8.09-8.14 (m, 2H), 7.97 (t, J=7.7 Hz, 1H), 7.65 (br s,4H), 6.76 (s, 1H), 6.52 (s, 1H), 6.51 (s, 1H), 3.86 (s, 2H), 3.78 (s,2H), 3.48 (s, 3H), 2.21 (s, 3H), 0.69 (m, 2H), 0.62 (m, 2H). Massspectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₂₀H₂₅N₃O₇S₂: 484.1 (M+H), 506.1 (M+Na). Found: 484.0, 506.0.

EXAMPLE 12{1-[[5-Methyl-3-(2-cyanophenylsulfonyloxy)phenoxy]methyl]cyclopropylmethoxy}guanidineacetate

a)1-[[3-(2-Cyanophenylsulfonyloxy)-5-methylphenoxy]methyl]cyclopropylmethanol

The title compound was prepared in 62% yield from3-(2-cyanophenylsulfonyloxy)-5-methylphenol, as prepared in step a ofExample 6, in a manner analogous to step b of Example 11. ¹H-NMR (300MHz, CDCl₃) δ8.09 (m, 1H), 7.80 (m, 2H), 6.66 (s, 1H), 6.60 (s, 1H),3.86 (s, 2H), 3.60 (s, 2H), 2.26 (s, 3H), 1.85 (br, s 1H), 0.62 (s, 4H).

b){1-[[3-(2-Cyanophenylsulfonyloxy)-5-methylphenoxy]ethyl]yclopropoxy}pthalimide

The title compound was prepared in 94% yield from1-[[3-(2-cyanophenylsulfonyloxy)-5-methylphenoxy]methyl]cyclopropylmethanol,as prepared in the preceding step, in a manner analogous to step c ofExample 11. ¹H-NMR (300 MHz, CDCl₃) (8.10 (m 1H), 7.95 (m, 1H), 7.78 (m,6H), 6.70 (s, 1H), 6.60 (s, 1H), 6.52 (s, 1H), 4.18 (s, 2H), 4.01 (s,2H), 2.28 (s, 3H), 0.70 (m, 4H).

c){1-[[3-(2-Cyanophenylsulfonyloxy)-5-methylphenoxy]methyl]cyclopropylmethoxy}amine

The title compound was prepared in 60% yield fromN-{1-[[3-(2-cyanophenylsulfonyloxy)-5-methylphenoxy]methyl]cyclopropoxy}phthalimide,as prepared in the preceding step, in a manner analogous to step d ofExample 11. ¹H-NMR (300 MHz, CDCl₃) (8.11 (m, 1H), 7.97 (m, 1H), 7.79(m, 2H), 6.66 (s, 1H), 6.58 (s, 1H), 6.56 (s, 1H), 5.30 (br s, 2H), 3.80(s, 2H), 3.64 (s, 2H), 2.26 (s, 3H), 0.63 (m, 4H).

d){1-[[5-Methyl-3-(2-cyanophenylsulfonyloxy)phenoxy]methyl]cyclopropylmethoxy}guanidineacetate

The title compound was prepared in 79% yield from{1-[[3-(2-cyanophenylsulfonyloxy)-5-methylphenoxy]methyl]cyclopropylmethoxy}amine,as prepared in the preceding step, in a manner analogous to step e ofExample 11. Flash column chromatography (100:10:1dichloromethane:methanol:acetic acid gave the title compound as anacetic acid salt. ¹H-NMR (300 MHz, DMSO-d₆) δ8.29 (d, J=7.0 Hz, 1H),8.02 (d, J=7.2 Hz, 1H), 7.98 (m, 2H), 6.77 (s, 1H), 6.47 (s, 1H), 6.42(s, 1H), 5.02 (br,s 4H), 3.80 (s, 2H), 3.56 (s, 2H), 2.21 (s, 3H), 1.89(s, 3H), 0.55 (s, 2H), 0.52 (s, 2H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₂₀H₂₂N₄O₅S: 431.1(M+H), 453.1 (M+Na). Found: 430.9, 452.8.

EXAMPLE 13{[[5-Methyl-3-(quinolinyl-8-sulfonyloxy)phenoxy]methyl]cyclopropylmethoxy}guanidineacetate

a)1-[[5-Methyl-3-(quinolinyl-8-sulfonyloxy)phenoxy]methyl]cyclopropylmethanol

The title compound was prepared in 73% yield from5-methyl-3-(quinolinyl-8-sulfonyloxy)phenol, as prepared in step a ofExample 3, in a manner analogous to step b of Example 11. ¹H-NMR (300MHz, CDCl₃) (9.26 (d, J=4.2 Hz, 1H), 8.42 (d, J=7.4 Hz, 1H), 8.30 (d,J=7.4 Hz, 1H),8.14 (d, J=7.3 Hz, 1H), 7.64 (s, 1H), 7.61 (t, J=4.2 H,1H), 6.55 (s, 1H), 6.46 (s, 2H), 3.73 (s, 2H), 3.55 (s, 2H), 2.16 (s,3H), 1.66 (br s, 1H), 0.58 (m, 4H).

b)N-{1-[[5-Methyl-3-(quinolinyl-8-sulfonyloxy)phenoxy]methyl]cyclopropoxy}phthalimide

The title compound was prepared in 89% yield from1-[[5-methyl-3-(quinolinyl-8-sulfonyloxy)phenoxy]methyl]cyclopropylmethanol,as prepared in the preceding step, in a manner analogous to step c ofExample 11. ¹H-NMR (300 MHz, CDCl₃) δ9.29 (d, J=4.3 Hz, 1H), 8.43 (d,J=7.4 Hz, 1H), 8.30 (d, J=7.4 Hz, 1H), 8.14 (d, J=7.2 Hz, 1H), 7.82 (m,2H), 7.75 (m, 2H), 7.62 (m, 2H), 6.59 (s, 1H), 6.50 (s, 1H), 6.42 (s,1H), 4.13 (s, 2H), 3.88 (s, 2H), 2.18 (s, 3H), 0.64 (s, 4H).

c){1-[[5-Methyl-3-(quinolinyl-8-sulfonyloxy)phenoxy]methyl]cyclopropylmethoxy}amine

The title compound was prepared in 79% yield fromN-{1-[[5-methyl-3-(quinolinyl-8-sulfonyloxy)phenoxy]methyl]cyclopropoxy}phthalimide,as prepared in the preceding step, in a manner analogous to step d ofExample 11. ¹H-NMR (300 MHz, CDCl₃) δ9.23 (d, J=4.2 Hz, 1H), 8.63 (d,J=7.4 Hz, 1H), 8.46 (d, J=7.3 Hz, 1H), 8.38 (d, J=7.3 Hz, 1H), 7.78 (m2H), 6.64 (s, 1H), 6.38 (s, 1H), 6.27 (s, 1H), 5.93 (br s, 2H), 3.59 (s,2H), 3.42 (s, 2H), 2.12 (s, 3H), 0.47 (m, 4H).

d){1-[[5-Methyl-3-(quinolinyl-8-sulfonyloxy)phenoxy]methyl]cyclopropylmethoxy}guanidineacetate

The title compound was prepared in 83% yield from{1-[[5-methyl-3-(quinolinyl-8-sulfonyloxy)phenoxy]methyl]cyclopropylmethoxy}amine,as prepared in the preceding step, in a manner analogous to step d ofExample 11. Flash column chromatography(100:10:1)dichloromethane:methanol:acetic acid) gave the title compoundas the acetic acid salt. ¹H-NMR (300 MHz, DMSO-d₆) δ9.23 (d, J=4.3 Hz,1H), 8.63 (d, J=8.3 Hz, 1H), 8.45 (d, J=8.3 Hz, 1H), 8.38 (d, J=7.4 Hz,1H), 7.78 (m, 2H), 6.64 (s, 1H), 6.38 (s, 1H), 6.27 (s, 1H), 5.25 (br s,4H), 3.65 (s, 2H), 3.53 (s, 2H), 2.12 (s, 3H), 1.89 (s, 3H), 0.55 (br s,2H), 0.44 (br s, 2H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₂₂H₂₄N₄O₅S: 457.2(M+H), 479.1 (M+Na). Found: 457.2, 479.0.

EXAMPLE 14{3-[5-Methyl-3-(2-morpholinylsulfonylphenylsulfonyloxy)phenoxy]propoxy}guanidinehydrochloride

a) 1-(Morpholinylsulfonyl)-2-nitrobenzene

To a solution of morpholine (1.91 g, 22 mmol and triethylamine (2.2 g,22 mmol) in dichloromethane (100 mL) at 0° C. was added2-nitrobenzenesulfonyl chloride (4.42 g, 20 mmol). The mixture wasstirred for 4 h and then additional dichloromethane (100 mL) was added.The dichloromethane solution was washed with saturated NaHCO₃ (2×50 mL),10% HCl (2×50 mL) and brine (50 mL) and dried over Na₂SO₄. Evaporatingthe solvent in vacuo gave the title compound as a yellow solid (5.3 g,97%). ¹H-NMR (300 MHz, CDCl₃) δ7.97 (d, J=7.3 Hz, 1H), 7.62-7.77 (m,3H), 3.75 (t, J=4.7 Hz, 4H), 3.30 (t, J=4.8 Hz, 4H).

b) 2-(Morpholinylsulfonyl)aniline

A mixture of 1-(morpholinylsulfonyl)-2-nitrobenzene (5.18 g, 19 mmol);as prepared in the preceding step, and 10% palladium on carbon (520 mg)in ethanol (80 mL) and tetrahydrofuran (80 mL) was stirred underhydrogen (balloon) for 5 h. The catalyst was removed by filtrationthrough Celite. The filtrate was concentrated to give the title compoundas a yellow solid (4.50 g, 98%) which was directly used for the nextstep without further purification.

c) 2-(Morpholinylsulfonyl)phenylsulfonyl chloride

The title compound was prepared in 47% yield from2-(morpholinylsulfonyl)aniline, as prepared in the preceding step, in amanner analogous to step a of Example 19. ¹H-NMR (300 MHz, CDCl₃) δ8.43(d, J=7.4 Hz, 1H), 8.24 (d, J=7.4 Hz, 1H), 7.88 (m, 2H), 3.74 (t, J=4.7Hz, 4H), 3.36 (t, J=4.7 Hz, 4H).

d) 5-Methyl-3-[2-(morpholinylsulfonyl)phenylsulfonyloxy]phenol

The title compound was prepared in 60% yield from2-(morpholinylsulfonyl)phenylsulfonyl chloride, as prepared in thepreceding step, in a manner analogous to step a of Example 1. ¹H-NMR(300 MHz, CDCl₃) (8.25 (d, J=7.8 Hz, 1H), 8.21 (d, J=7.8 Hz, 1H), 7.80(t, J=6.3 Hz, 1H), 7.70 (t, J=6.4 Hz, 1H), 6.60 (s, 1H), 6.49 (s, 1H),3.73 t, J=4.7 Hz, 4H), 3.36 (t, J=4.7 Hz, 4H), 2.24 (s, 3H).

e)3-{5-Methyl-3-[(2-morpholinylsulfonyl)phenylsulfonyloxy]phenoxy}propanol

The title compound was prepared in 83% yield from5-methyl-3-[2-(morpholinylsulfonyl)phenylsulfonyloxy]phenol, as preparedin the preceding step, in a manner analogous to step b of Example 10.¹H-NMR (300 MHz, CDCl₃) δ8.25 (d, J=7.8 Hz, 1H), 8.21 (d, J=7.8 Hz, 1H),7.81 (t, J=7.7 Hz, 1H), 7.70 (t, J=7.6 Hz, 1H), 6.60 (s, 2H), 6.56 (s,1H), 4.36 (t, J=6.7 Hz, 2H), 4.11 (t, J=7.0 Hz, 2H), 3.75 (t, J=4.7 Hz,4H), 3.35 (t, J=4.7 Hz, 4H), 2.24 (s, 3H) 2.05 (t, J=7.0 Hz, 2H).

f)N-{3-[5-Methyl-[3-(2-morpholinylsulfonyl)phenylsulfonyloxy]phenoxy]propoxy}phthalimide

The title compound was prepared in 83% yield from3-}5-methyl-3-[(2-morpholinylsulfonyl)phenylsulfonyloxy]phenoxy}propanol,as prepared in the preceding step, in a manner analogous to step d ofExample 1. ¹H-NMR (300 MHz, CDCl₃) δ8.28 (d, J=7.8 Hz, 1H), 8.21 (d,J=7.8 Hz, 1H), 7.68-7.86 (m, 6H), 6.63 (s, 1H), 6.59 (s, 1H), 6.51 (s,1H), 4.36 (t, J=6.7 Hz, 2H), 4.11 (t, J=7.0 Hz, 2H), 3.72 (t, J=4.7 Hz,4H), 3.36 (t, J=4.7 Hz, 4H), 2.25 (s, 3H), 2.18 (t, J=6.4 Hz, 2H).

g)3-[5-Methyl-[3-(2-morpholinylsulfonyl)phenylsulfonyloxy]phenoxy]propoxyamine

The title compound was prepared in 95% yield fromN-{3-[5-methyl-[3-(2-morpholinylsulfonyl)phenylsulfonyloxy]phenoxy]propoxy}phthalimide,as prepared in the preceding step, in a manner analogous to step e ofExample 1. ¹H-NMR (300 MHz, CDCl₃) (8.26 (d, J=7.9 Hz, 1H), 8.20 (d,J=7.8 Hz, 1H), 7.81 (t, J=7.7 Hz, 1H), 7.70 (t, J=7.7 Hz, 1H), 6.59 (s,1H), 6.57 (s, 1H), 6.54 (s, 1H), 3.93 (t, J=6.3 Hz, 2H), 3.79 (t, J=6.2Hz, 2H), 3.73 (t, J=4.7 Hz, 4H), 3.36 (t, J=4.7 Hz, 4H), 2.25 (s, 3H),2.00 (t, J=6.3 Hz, 2H).

h){3-[5-Methyl-3-(2-morpholinylsulfonylphenylsulfonyloxy)phenoxy]propoxy}guanidinehydrochloride

The title compound was prepared in 95% yield from3-[5-methyl-[3-(2-morpholinylsulfonyl)phenylsulfonyloxy]phenoxy]propoxyamine,as prepared in the preceding step, in a manner analogous to step f ofExample 1. ¹H-NMR (300 MHz, DMSO-d₆) δ8.21 (t, J=8.0 Hz, 2H), 8.04 (t,J=7.8 Hz, 1H), 7.92 (t, J=7.8 Hz, 1H), 7.71 (br s, 4H), 6.75 (s, 1H),6.53 (s, 1H), 6.49 (s, 1H), 3.99 (t, J=6.3 Hz, 2H), 3.90 (t, J=6.4 Hz,2H), 3.62 (t, J=4.7 Hz, 4H), 3.25 (t, J=4.7 Hz, 4H), 2.22 (s, 3H), 2.02(t, J=6.3 Hz, 2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamicacid matrix) calcd. for C₂₁H₂₈N₄O₈S₂: 529.1 (M+H), 551.1 (M+Na). Found:528.9, 550.8.

EXAMPLE 15{3-[5-Methyl-3-(2-(acetylpiperazinykulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidinehydrochloride

a) 1-(Acetylpiperazinylsulfonyl)-2-nitrobenzene

The title compound was prepared in 87% yield from acetylpiperazine in amanner analogous to step a of Eg. 14. ¹H-NMR (300 MHz, CDCl₃) δ7.99 (d,J=6.8 Hz, 1H), 7.74 (m, 2H), 7.64 (d, J=6.8 Hz, 1H), 3.70 (t, J=5.1 Hz,2H), 3.57 (t, J=5.0 Hz, 2H), 3.35 (t, J=5.0 Hz, 2H), 3.27 (t, J=5.21 Hz,2H), 2.10 (s, 3H).

b) 2-(Acetylpiperazinylsulfonyl)aniline

The title compound was prepared in 80% yield from1-(acetylpiperazinylsulfonyl)-2-nitrobenzene, as prepared in thepreceding step, in a manner analogous to step b of Example 14. Thiscompound was directly used for next step without further purification.

c) 2-(Acetylpiperazinylsulfonyl)phenylsulfonyl chloride

The title compound was prepared in 46% yield from2-(acetylpiperazinylsulfonyl)aniline, as prepared in the preceding step,in a manner analogous to step a of Example 19. ¹H-NMR (300 MHz, CDCl₃)δ8.42 (d, J=7.2 Hz, 1H), 8.27 (d, J=7.3 Hz, 1H), 7.89 (m, 2H), 3.27-3.68(m, 8H), 2.10 (s, 3H).

d) 5-Methyl-3-[2-(acetylpepiperazinylsulfonyl)phenylsulfonyloxy]phenol

The title compound was prepared in 44% yield from2-(acetylpiperazinylsulfonyl)phenylsulfonyl chloride, as prepared in thepreceding step, in a manner analogous to step a of Eg.1. ¹H-NMR (300MHz, CDCl₃) δ8.26 (d, J=7.8 Hz, 1H), 8.17 (d, J=7.8 Hz, 1), 7.81 (t,J=7.7 Hz, 1H), 7.70 (t, J=7.6 Hz, 1H), 7.16 (s, 1H), 6.55 (s, 1H), 6.51(s, 1H), 6.45 (s, 1H), 3.68 (t, J=4.8 Hz, 2H), 3.55 (m, 2H), 3.46 (m,2H), 3.29 (t, J=4.9 Hz, 2H), 2.21 (s, 3H), 2.09 (s, 3H).

e)3-{5-Methyl-3-[2-(acetylpiperazinylsulfonyl)phenylsulfonyloxy]phenoxy}propanol

The title compound was prepared in 76% yield from5-methyl-3-[2-(acetylpepiperazinylsulfonyl)phenylsulfonyloxy]phenol, asprepared in the preceding step, in a manner analogous to step b ofExample 10. ¹H-NMR (300 MHz, CDCl₃) δ8.29 (d, J=7.8 Hz, 1H), 8.19 (d,J=7.8 Hz, 1H), 7.82 (t, J=7.7 Hz, 1H), 7.71 (t, J=7.7 Hz, 1H), 6.61 (s,1H), 6.56 (s, 1H), 6.53 (s, 1H), 4.00 (t, J=6.0 Hz, 2H), 3.78 (m, 2H),3.65 (m, 2H), 3.62 (m, 2H), 3.54 (m, 2H), 3.30 (m, 2H), 2.24 (s, 3H),2.08 (s, 3H), 1.97 (t, J=6.0 Hz, 2H).

f)N-{3-[5-Methyl-3-[2-(acetylpiperazinylsulfonyl)phenylsulfonyloxy]phenoxy]propoxy}phthalimide

The title compound was prepared in 89% yield from3-{5-methyl-3-[2-(acetylpiperazinylsulfonyl)phenylsulfonyloxy]phenoxy}propanol,as prepared in the preceding step, in a manner analogous to step d ofExample 1. ¹H-NMR (300 MHz, CDCl₃) δ8.31 (d, J=7.8 Hz, 1H), 8.18 (d,J=7.8 Hz, 1H), 7.44-7.86 (m, 6H), 6.63 (s, 1H), 6.57 (s, 1H), 6.49 (s,1H), 4.36 (d, J=6.1 Hz, 2H), 4.10 (t, J=6.0 Hz, 2H), 3.67 (m 2H), 3.54(m, 2H), 3.48 (m, 2H), 3.28 (m, 2H), 2.25 (s, 3H), 2.18 (t, J=6.1 Hz,2H), 2.08 (s, 3H).

g)3-[5-Methyl-3-2-(acetylpiperazinylsulfonyl)phenylsulfonyloxy]phenoxy]propoxyamine

The title compound was prepared in 73% yield fromN-{3-[5-methyl-3-[2-(acetylpiperazinylsulfonyl)phenylsulfonyloxy]phenoxy]propoxy}phthalimide,as prepared in the preceding step, in a manner analogous to step e ofExample 1. ¹H-NMR (300 MHz, CDCl₃) δ8.29 (d, J=7.9 Hz, 1H), 8.18 (d,J=7.8 Hz, 1H), 7.82 (t, J=7.8 Hz, 1H), 7.70 (t, J=7.8 Hz, 1H), 6.60 (s,1H), 6.54 (s, 1H), 6.52 (s, 1H), 3.92 (t, J=6.3 Hz, 2H), 3.79 (t, J=6.2Hz, 2H), 3.67 (t, J=5.5 Hz, 2H), 3.55 (t, J=6.0 Hz, 2H), 3.48 (t, J=5.8Hz, 2H), 3.30 (t, J=5.6 Hz, 2H), 2.24 (s, 3H), 2.08 (s, 3H), 2.00 (t,J=6.2 Hz, 2H).

h){3-[5-Methyl-3-[2-(acetylpiperazinylsulfonyl)phenylsulfonyloxy]phenoxy]propoxy}guanidinehydrochloride

The title compound was prepared in 84% yield from3-[5-methyl-3-[2-(acetylpiperazinylsulfonyl)phenylsulfonyloxy]phenoxy]propoxyamine,as prepared in the preceding step, in a manner analogous to step f ofExample 1. ¹H-NMR (300 MHz, DMSO-d₆)δ11.11 (br s, 1H), 8.19 (t, J=7.9Hz, 2H), 8.03 (t, J=7.7 Hz, 1H), 7.91 (t, J=7.7 Hz 1H), 7.71 (br s, 4H),6.75 (s, 1H), 6.53 (s, 1H), 6.49 (s, 1H), 3.99 (t, J=6.2 Hz, 2H), 3.90(t, J=6.3 Hz, 2H), 3.50 (m, 4H), 3.32 (m, 2H), 3.24 (m, 2H), 2.22 (s,3H), 2.04 (t, J=6.2 Hz, 2H), 1.99 (s, 3H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₂₃H₃₁N₅O₈S₂: 570.2(M+H), 592.2 (M+Na). Found: 570.2, 592.2.

EXAMPLE 16{3-[5-Methyl-3-(2-(N-methylphenethylaminosulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidinehydrochloride

a) 1-(N-Methylphenethylaminosulfonyl)-2-nitrobenzene

The title compound was prepared in 94% yield from N-methylphenethylaminein a manner analogous to step a of Example 14. ¹H-NMR (300 MHz, CDCl₃)δ7.93 (d, J=7.7 Hz, 1H), 7.56-7.68 (m, 3H), 7.18-7.31 (m, 5H), 3.47 (t,J=7.8 Hz, 2H), 2.92 (s, 3H), 2.90 (t, J=7.6 Hz, 2H).

b) 2-(N-Methylphenethylaminosulfonyl)aniline

The title compound was prepared in 95% yield from1-(N-methylphenethylaminosulfonyl)-2-nitrobenzene, as prepared in thepreceding step, in a manner analogous to step b of Example 14. Thiscompound was directly used for next step with further purification.

c) 2-(N-Methylphenethylaminosulfonyl)phenylsulfonyl chloride

The title compound was prepared in 40% yield from2-(N-methylphenethylaminosulfonyl)aniline, as prepared in the precedingstep, in a manner analogous to step a of Example 19. ¹H-NMR (300 MHz,CDCl₃) δ7.93 (d, J=7.7 Hz, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.7 (t, J=7.6Hz, 2H), 7.18-7.31 (m, 5H), 3.50 (t, J=7.8 Hz, 2H), 2.94 (s, 3H), 2.90(t, J=7.6 Hz, 2H).

d)5-Methyl-3-[2-(N-methylphenethylaminosulfonyl)phenylsulfonyloxy]phenol

The title compound was prepared in 24% yield from2-(N-methylphenethylaminosulfonyl)phenylsulfonyl chloride, as preparedin the preceding step, in a manner analogous to step a of Eg. 1. ¹H-NMR(300 MHz, CDCl₃) δ8.18 (d, J=7.8 Hz, 1H), 8.12 (d, J=7.8 Hz, 1H), 7.73(t, J=7.7 Hz, 1H), 7.63 (t, J=7.7 Hz, 1H), 7.17-7.29 (m, 5H), 6.59 (s,1H), 6.53 (s, 1H), 6.49 (s, 1H), 3.56 (t, J=7.8 Hz, 2H), 2.96 (s, 3H),2.92 (t, J=7.7 Hz, 2H), 2.22 (s, 3H).

e)3-{5-Methyl-3-[2-(N-methylphenethylaminosulfonyl)phenylsulfonyloxy]phenoxy}propanol

The title compound was prepared in 73% yield from5-methyl-3-[2-(N-methylphenethylaminosulfonyl)phenylsulfonyloxy]phenol,as prepared in the preceding step, in a manner analogous to step b ofExample 10. ¹H-NMR (300 MHz, CDCl₃) δ8.20 (d, J=7.9 Hz, 1H), 8.13 (d,J=7.8 Hz, 1H), 7.74 (t, J=7.7 Hz, 1H), 7.63 (t, J=7.7 Hz, 1H), 7.17-7.29(m, 5H), 6.59 (s, 1H), 6.57 (s, 1H), 6.53 (s, 1H), 3.99 (t, J=6.0 Hz,2H), 3.80 (t, J=5.9 Hz, 2H), 3.55 (t, J=7.8 Hz, 2H), 2.97 (s, 3H), 2.92(t, J=7.7 Hz, 2H), 2.22 (s, 3H), 1.96 (t, J=6.0 Hz, 2H).

f)N-{3-[5-Methyl-3-[2-N-methylphenethylaminosulfonyl)phenylsulfonyloxy]phenoxy]propoxy}phthalimide

The title compound was prepared in 63% yield from3-{5-methyl-3-[2-(N-methylphenethylaminosulfonyl)phenylsulfonyloxy]phenoxy}propanol,as prepared in the preceding step, in a manner analogous to step d ofExample 1. ¹H-NMR (300 MHz, CDCl₃) δ8.22 (d, J=7.8 Hz, 1H), 8.13 (d,J=7.8 Hz, 1H), 7.83 (m, 2H), 7.74 (m, 3H), 7.63 (t, J=7.7 Hz, 1H),7.17-7.29 (m, 5H), 6.62 (s, 1H), 6.59 (s, 1H), 6.52 (s, 1H), 4.35 (t,J=6.0 Hz, 2H), 4.08 (t, J=6.1 Hz, 2H), 3.57 (t, J=7.8 Hz, 2H), 2.97 (s,3H), 2.92 (t, J=7.7 Hz, 2H), 2.24 (s, 3H), 2.17 (t, J=6.0 Hz, 2H).

g)3-[5-Methyl-[3-(2-N-methylphenethylaminosulfonyl)phenylsulfonyloxy]phenoxy]propoxyamine

The title compound was prepared in 90% yield fromN-{3-[5-methyl-3-[2-(N-methylphenethylaminosulfonyl)phenylsulfonyloxy]phenoxy]propoxy}phthalimide,as as prepared in the preceding step, in a manner analogous to step e ofExample 1. ¹H-NMR (300 MHz, CDCl₃) δ8.21 (d, J=7.9 Hz, 1H), 8.13 (d,J=7.9 Hz, 1H), 7.74 (t, J=7.8 Hz, 2H), 7.62 (t, J=7.7 Hz, 1H), 7.17-7.29(m, 5H), 6.58 (s, 2H), 6.55 (s, 1H), 3.91 (t, J=6.2 Hz, 2H), 3.80 (t,J=6.1 Hz, 2H), 3.57 (t, J=7.8 Hz, 2H), 2.97 (s, 3H), 2.92 (t, J=7.7 Hz,2H), 2.23 (s, 3H), 1.99 (t, J=6.2 Hz, 2H).

h){3-[5-Methyl-3-(2-(N-methylphenethylaminosulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidinehydrochloride

The title compound was prepared in 84% yield from3-[5-methyl-3-[2-(N-methylphenethylaminosulfonyl)phenylsulfonyloxy]phenoxy]propoxyamine,as prepared in the preceding step, in a manner analogous to step f ofExample 1. ¹H-NMR (300 MHz, DMSO-d₆) δ11.01 (br s, 1H), 8.14 (d, J=7.9Hz, 1H), 8.07 (d, J=7.9 Hz, 1H), 7.97 (t, J=7.8 Hz, 2H), 7.86 (t, J=7.7Hz, 1H), 7.63 (br s, 4H), 7.17-7.29 (m, 5H), 6.74 (s, 1H), 6.54 (s, 1H),6.51 (s, 1H), 3.98 (t, J=6.2 Hz, 2H), 3.90 (t, J=6.1 Hz, 2H), 3.53 (t,J=7.8 Hz, 2H), 2.94 (s, 3H), 2.87 (t, J=7.7 Hz, 2H), 2.21 (s, 3H), 2.01(t, J=6.2 Hz, 2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamicacid matrix) calcd. for C₂₃H₃₁N₅O₈S₂: 577.2 (M+H), 599.2 (M+Na). Found:577.1, 599.0.

EXAMPLE 17{3-[5-Methoxy-3-(2-methylsulfonylphenylsulfonyloxy)phenoxy]propoxy}guanidinehydrochloride

a) 5-Methoxy-3-[2-(methylsulfonyl)phenylsulfonyloxy]phenol

The title compound was prepared in 80% yield from2-methylsulfonylbenzenesulfonyl chloride and 5-methoxyresorcinol in amanner analogous to step a of Example 1. ¹H-NMR (300 MHz, CDCl₃) δ8.42(d, J=7.8 Hz, 1H), 8.13 (d, J=7.8 Hz, 1H), 7.88 (t, J=7.8 Hz, 1H), 7.75(t, J=7.7 Hz, 1H), 6.36 (s, 1H), 6.31 (s, 1H), 6.28 (s, 1H), 3.68 (s,3H), 3.45 (s, 3H).

b) 3-{5-Methoxy-3-[2-(methylsulfonyl)phenylsulfonyloxy]phenoxy}propanol

The title compound was prepared in 72% yield from5-methoxy-3-[2-(methylsulfonyl)phenylsulfonyloxy]phenol, as prepared inthe preceding step, in a manner analogous to step a of Example 10.¹H-NMR (300 MHz, CDCl₃) δ8.44 (d, J=7.8 Hz, 1H), 8.14 (d, J=7.8 Hz, 1H),7.88 (t, J=7.7 Hz, 1H), 7.75 (t, J=7.7 Hz, 1H), 6.40 (s, 1H), 6.38 (s,1H), 6.33 (s, 1H), 4.13 (t, J=6.3 Hz, 2H), 3.99 (t, J=6.0 Hz, 2H), 3.69(s, 3H), 3.45 (s, 3H), 1.97 (t, J=6.0 Hz, 2H), 1.67 (br s, 1H).

c)N-{3-[5-Methoxy-3-[2-(methylsulfonyl)phenylsulfonyloxy]phenoxy]propoxy}phthalimide

The title compound was prepared in 88% yield from3-{5-methoxy-3-[2-(methylsulfonyl)phenylsulfonyloxy]phenoxy}propanol, asprepared in the preceding step, in a manner analogous to step d ofExample 1. ¹H-NMR (300 MHz, CDCl₃) δ8.45 (d, J=7.8 Hz, 1H), 8.14 (d,J=7.8 Hz, 1H), 7.74-7.89 (m, 6H), 6.37 (s, 3H), 4.46 (t, J=6.2 Hz, 2H),4.10 (t, J=6.1 Hz, 2H), 3.69 (s, 3H), 3.45 (s, 3H), 2.18 (t, J=6.1 Hz,2H).

d)3-[5-Methoxy-3-[2-(methylsulfonyl)phenylsulfonyloxy]phenoxy]propoxyamine

The title compound was prepared in 79% yield fromN-{3-[5-methoxy-3-[2-(methylsulfonyl)phenylsulfonyloxy]phenoxy]propoxy}phthalimide,as prepared in the preceding step, in a manner analogous to step e ofExample 1. ¹H-NMR (300 MHz, CDCl₃) δ8.45 (d, J=7.8 Hz, 1H), 8.13 (d,J=7.8 Hz, 1H), 7.88 (t, J=7.7 Hz, 1H), 7.75 (t, J=7.7 Hz, 1H), 6.38 (s,1H), 6.36 (s, 1H), 6.32 (s, 1H), 5.40 (br s, 2H), 3.92 (t, J=6.3 Hz,2H), 3.78 (t, J=6.1 Hz, 2H), 3.69 (s, 3H), 3.45 (s, 3H), 1.99 (t, J=6.2Hz, 2H).

e){3-[5-Methoxy-3-(2-methylsulfonylphenylsulfonyloxy)phenoxy]propoxy}guanidinehydrochloride

The title compound was prepared in 71% yield from3-[5-methoxy-3-[2-(methylsulfonyl)phenylsulfonyloxy]phenoxy]propoxyamine,as prepared in the preceding step, in a manner analogous to step f ofExample 1. ¹H-NMR (300 MHz, DMSO-d₆) δ11.14 (br s, 1H), 8.37 (d, J=7.8Hz, 1H), 8.13 (m, 2H), 7.97 (t, J=7.7 Hz, 1H), 7.71 (br,s 4H), 6.48 (s,1H), 6.31 (s, 1H), 6.26 (s, 1H), 3.99 (t, J=6.2 Hz, 2H), 3.90 (t, J=6.3Hz, 2H), 3.66 (s, 3H), 3.47 (s, 3H), 2.01 (t, J=6.2 Hz, 2H). Massspectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₁₈H₂₃N₃O₈S₂: 474.1 (M+H), 496.1 (M+Na). Found: 474.0, 496.0.

EXAMPLE 18{3-[5-Ethyl-3-(2-methylsulfonylphenylsulfonyloxy)phenoxy]propoxy}guanidinehydrochloride

a) 5-Ethyl-3-[2-(methylsulfonyl)phenylsulfonyloxy]phenol

The title compound was prepared in 89% yield from2-methylsulfonylbenzenesulfonyl chloride and 5-ethylresorcinol in amanner analogous to step a of Eg. 1. ¹H-NMR (300 MHz, CDCl₃) δ8.43 (d,J=7.8 Hz, 1H), 8.09 (d, J=7.8 Hz, 1H), 7.87 (t, J=7.8 Hz, 1H), 7.73 (t,J=7.7 Hz, 1H), 6.56 (s, 2H), 6.52 (s, 1H), 5.59 (br s, 1H), 3.45 (s,3H), 2.49 (q, J=7.6 Hz, 2H), 1.09 (t, J=7.6 Hz, 3H).

b) 3-{5-Ethyl-3-[2-(methylsulfonyl)phenylsulfonyloxy]phenoxy}propanol

The title compound was prepared in 82% yield from5-ethyl-3-[2-(methylsulfonyl)phenylsulfonyloxy]phenol, as prepared inthe preceding step, in a manner analogous to step b of Example 10.¹H-NMR (300 MHz, CDCl₃) δ8.45 (d, J=7.8 Hz, 1H), 8.10 (d, J=7.8 Hz, 1H),7.88 (t, J=7.7 Hz, 1H), 7.73 (t, J=7.8 Hz, 1H), 6.62 (s, 1H), 6.61 (s,1H), 6.57 (s, 1H), 4.01 (t, J=6.0 Hz, 2H), 3.82 (t, J=6.0 Hz, 2H), 3.45(s, 3H), 2.51 (q, J=7.6 Hz, 2H), 1.09 (t, J=7.6 Hz, 3H).

c)N-{3-[5-Ethyl-3-[2-(methylsulfonyl)phenylsulfonyloxy]phenoxy]propoxy}phthalimide

The title compound was prepared in 97% yield from3-{5-ethyl-3-[(2-methyl-sulfonyl)phenylsulfonyloxy]phenoxy}propanol, asprepared in the preceding step, in a manner analogous to step d ofEg. 1. ¹H-NMR (300 MHz, CDCl₃) δ8.45 (d, J=7.8 Hz, 1H), 8.10 (d, J=7.8Hz, 1H), 7.74-7.90 (m, 6H), 6.65 (s, 1H), 6.57 (s, 2H), 4.37 (t, J=6.2Hz, 2H), 4.12 (t, J=6.1 Hz, 2H), 3.46 (s, 3H), 2.51 (q, J=7.6 Hz, 2H),1.10 (t, J=7.6 Hz, 3H).

g)3-[5-Ethyl-3-[2-(methylsulfonyl)phenylsulfonyloxy]phenoxy]propoxyamine

The title compound was prepared in 78% yield fromN-{3-[5-ethyl-3-[2-(methylsulfonyl)phenylsulfonyloxy]phenoxy]propoxy}phthalimide,as prepared in the preceding step, in a manner analogous to step e ofExample 1. ¹H-NMR (300 MHz, CDCl₃) δ8.45 (d, J=7.8 Hz, 1H), 8.09 (d,J=7.8 Hz, 1H), 7.87 (t, J=7.7 Hz, 1H), 7.73 (t, J=7.7 Hz, 1H), 6.61 (s,1H), 6.59 (s, 1H), 6.56 (s, 1H), 3.93 (t, J=6.2 Hz, 2H), 3.81 (t, J=6.1Hz, 2H), 3.45 (s, 3H), 2.50 (q, J=7.6 Hz, 2H), 1.09 (t, J=7.6 Hz, 3H).

h){3-[5-Ethyl-3-(2-methylsulfonylphenylsulfonyloxy)phenoxy]propoxy}guanidinehydrochloride

The title compound was prepared in 82% yield from3-[5-ethyl-3-[2-(methylsulfonyl)phenylsulfonyloxy]phenoxy]propoxyamine,as prepared in the preceding step, in a manner analogous to step f ofExample 1. ¹H-NMR (300 MHz, DMS0-d₆) δ11.17 (br s, 1H), 8.37 (d, J=7.8Hz, 1H), 8.08 (m, 2H), 7.95 (t, J=7.6 Hz, 1H), 7.73 (br s, 4H), 6.77 (s,1H), 6.54 (s, 1H), 6.48 (s, 1H), 4.00 (t, J=6.2 Hz, 2H), 3.91 (t, J=6.3Hz, 2H), 3.47 (s, 3H), 2.50 (q, J=7.6 Hz, 2H), 1.02 (t, J=7.6 Hz, 3H).Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd.for C₁₉H₂₅N₃O₇S₂: 472.1 (M+H), 494.1 (M+Na), 510.1 (M+K). Found: 472.0,493.9, 509.9.

EXAMPLE 19{3-[5-Methyl-3-(2-(phenylsulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidinehydrochloride

a) 2-(Phenylsulfonyl)benzenesulfonyl chloride

To a solution of 2-(phenylsulfonyl)aniline (2.33 g, (10 mmol) in 30%aqueous hydrochloric acid (4 mL) was added 40% aqueous sodium nitrite (4mL) at 0-5° C. After 15 minute, to the diazo solution were added 30%aqueous hydrochloric acid (10 mL), cooper sulfate (50 mg) and 40%aqueous sodium bisulfite (10 mL) at 5-10° C. The mixture was stirred for30 minutes and additional water (30 mL) was added. The mixture wasextracted into dichloromethane (3×40 mL) and the dichloromethanesolution was washed with brine (40 mL) and dried over Na₂SO₄. Afterremoving the solvent in vacuo, the residue was purified by flash columnchromatography (dichloromethane) to give the title compound as a whitesolid (2.1 g, 66%). ¹H-NMR (300 MHz, CDCl₃) δ8.62 (d, J=7.8 Hz, 1H),8.34 (d, J=7.9 Hz, 1H), 7.85-7.98 (m, 4H), 7.48-7.63 (m, 3H).

b)N,N′-(Bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-(2-(phenylsulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidine

To a solution of(N,N′-bis-tert-butyloxycarbonyl)-{3-[(3-hydroxy-5-methyl)phenoxy)propoxy}guanidine(88 mg, 0.2 mmol), as prepared in step f of Example 20, andtriethylamine (0.2 mL) in dichloromethane (10 mL) was added2-(phenylsulfonyl)benzenesulfonyl chloride (64 mg, 0.2 mmol), asprepared in the preceding step. The mixture was stirred at ambienttemperature for 2 h. Additional dichloromethane (50 mL) was added. Thedichloromethane solution was washed with 10% citric acid (2×30 mL) andbrine (30 mL) and dried over Na₂SO₄. After removing the solvent, theresidue was purified on a Waters Sep-Pak (10 g silica, dichloromethane)to give the title compound as a colorless foam (109 mg, 75%). ¹H-NMR(300 MHz, CDCl₃) δ9.08 (s, 1H), 8.64 (d, J=7.9 Hz, 1H), 8.07 (d, J=7.8Hz, 1H), 7.97 (d, J=7.9 Hz, 2H), 7.89 (t, J=7.8 Hz, 1H), 7.71 (t, J=7.8Hz, 2H), 7.56 (d, J=7.2 Hz, 1H), 7.49 (t, J=7.1 Hz, 2H), 6.59 (s, 1H),6.57 (s, 1H), 6.53 (s, 1H), 3.19 (t, J=6.2 Hz, 2H), 3.94 (t, J=6.2 Hz,2H), 2.91 (s, 3H), 2.23 (s, 3H), 2.11 (t, J=6.2 Hz, 2H), 1.49 (s, 18H).

c){3-[5-Methyl-3-(2-(phenylsulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidinehydrochloride

To a solution ofN,N′-(bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-(2-phenylsulfonylphenylsulfonyloxy)phenoxy]propoxy}guanidine(108 mg, 0.15 mmol), as prepared in the preceding step, indichloromethane (5 mL) was added trifluoroacetic acid (2 mL). Themixture was stirred at ambient temperature for 3 h and then the solventwas evaporated in vacuo. The residue was dissolved in dichloromethane(50 mL), washed with 2 N K₂CO₃ (2×30 mL) and dried over Na₂SO₄. Afterthe solvent was evaporated, the residue was converted to the HCl saltwith methanolic HCl and purified on a Waters Sep-Pak (5 g silica, 10%methanol in dichloromethane) to give the title compound as a colorlessfoam (78 mg, 93%). ¹H-NMR (300 MHz, DMSO-d₆) δ11.05 (br s, 1H), 8.62 (d,J=7.9 Hz, 1H), 8.13 (m, 2H), 7.98 (d, J=8.1 Hz, 1H), 7.93 (m, 2H), 7.69(d, J=7.6 Hz, 1H), 7.60 (t, J=7.8 Hz, 2H), 7.20 (br s, 4H), 6.74 (s,1H), 6.47 (s, 1H), 6.45 (s, 1H), 3.98 (t, J=6.3 Hz, 2H), 3.88 (t, J=6.3Hz, 2H), 2.91 (s, 3H), 2.21 (s, 3H), 2.00 (t, J=6.3 Hz, 2H). Massspectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₂₃H₂₅N₃O₇S₂: 520.1 (M+H), 542.1 (M+Na). Found: 520.3, 542.2.

EXAMPLE 20{3-[5-Methyl-3-(2-(4-ethyloxycarbonyl)piperidinylsulfonylphenylsulfonyloxy)phenoxy]propoxy}guanidinehydrochloride

a) 3-Benzyloxy-5-methylphenol

Orcinol monohydrate (7.10 g, 50 mmol) in N,N-dimethylformamide (20 mL)was added dropwise to a mixture of NaH (95%, 24 g, 100 mmol) inN,N-dimethylformamide (60 mL) and the mixture was stirred at roomtemperature for 20 min. Benzyl bromide (8.55 g, 50 mmol) inN,N-dimethylformamide (20 mL) was added dropwise to the mixture andstirred at room temperature for 2 hours. Water (100 mL) was added slowlyto the reaction mixture. The reaction mixture was extracted with ethylacetate (3×100 mL) and then the organic phase was washed with brine(2×50 mL) and dried over Na₂SO₄. After the solvent was evaporated, theresidue was purified by flash column chromatography (silica gel, 3:1hexane:ethyl acetate) to give the title compound as a yellow oil (5.20g, 48%). ¹H-NMR (300 MHz, CDCl₃) δ7.39 (m, 5H), 6.40 (s, 1H), 6.29 (t,J=5.3 Hz, 1H), ), 6.26 (s, 1H), 5.25 (s, 1H), 4.99 (s, 2H), 2.26 (s,3H).

b) 3-[(3-Benzyloxy-5-methyl)phenoxy]propanol

3-Benzyloxy-5-methylphenol (5.20 g, 24 mmol), as prepared in thepreceding step, was stirred with 3-bromopropanol (3.6 g, 26 mmol) andCs₂CO₃ (8.2 g, 25 mmol) in acetonitrile (80 mL) at 50° C. overnight.After cooling to room temperature, the solid was removed by filtration.The filtrate was concentrated in vacuo and the residue was purified byflash column chromatography (1:2 to 1:1 ethyl acetate:hexane) to givethe title compound as a yellow oil (4.3 g, 66%). ¹H-NMR (300 MHz, CDCl₃)δ7.38 (m, 5H), 6.41 (s, 1H), 6.36 (s, 2H), 5.01 (s, 2H), 4.07 (t, J=6.3Hz, 2H), 3.83 (t, J=6.0 Hz, 2H), 2.29 (s, 3H), 2.05 (m, 2H).

c) N-{3-[(3-Benzyloxy-5-methyl)phenoxy]propoxy}phthalimide

To a solution of 3-[(3-benzyloxy-5-methyl)phenoxy]propanol (4.2 g, 15.0mmol), as prepared in the preceding step, triphenylphosphine (4.5 g,17.0 mmol) and N-hydroxyphthalimide (2.8 g, 17.0 mmol) intetrahydrofuran (100 mL) was added diethyl azodicarboxylate (3.0 g, 17.0mmol) at 0° C. The reaction mixture was stirred at ambient temperatureovernight. The reaction mixture was concentrated in vacuo and ethylacetate (100 mL) was added to the residue. The solid was removed byfiltration and the filtrate was concentrated in vacuo. The residue waspurified by flash column chromatography (dichloromethane) to give thetitle compound as a pale yellow oil (5.0 g, 89%). ¹H-NMR (300 MHz,CDCl₃) δ7.82 (d, J=8.2 Hz, 2H), 7.74 (d, J=8.3 Hz, 2H), 7.38 (m, 5H),6.41 (s, 1H), 6.39 (s, 1H), 6.38 (s, 1H), 5.02 (s, 2H), 4.40 (t, J=6.3Hz, 2H), 4.19 (t, J=6.1 Hz, 2H), 2.29 (s, 3H), 2.23 (t, J=6.2 Hz, 2H).

d) {3-[(3-Benzyloxy-5-methyl)phenoxy]propoxy}amine

N-{3-[(3-Benzyloxy-5-methyl)phenoxy]propoxy}phthalimide (2.25 g, 6.0mmol), as prepared in the preceding step, was stirred with 40% aqueousmethylamine (4.8 mL, 60 mmol) in ethanol (60 mL) and tetrahydrofuran (20mL) for 1 h. The reaction mixture was concentrated in vacuo to give awhite solid. Flash column chromatography (20% ethyl acetate indichloromethane) gave the title product as a colorless oil (1.40 g,82%). ¹H-NMR (300 MHz, CDCl₃) δ7.40 (m, 5H), 6.41 (s, 1H), 6.36 (s, 2H),5.35 (br s, 2H), 5.00 (s, 2H), 4.00 (t, J=6.3 Hz, 2H), 3.83 (t, J=6.2Hz, 2H), 2.29 (s, 3H), 2.04 (t, J=6.3 Hz, 2H).

e)(N,N′-Bis-tert-butyloxycarbonyl)-{3-[(benzyloxy-5-methyl)phenoxy]propoxy}guanidine

To a solution of 3-[(3-benzyloxy-5-methyl)phenoxy]propoxyamine (1.75 g,6.0 mmol), as prepared in the preceding step, in N,N-dimethylformamide(20 mL) was added(N,N′-bis-tert-butyloxycarbonyl)-1H-pyrazole-carboxamidine (2.2 g, 7.0mmol). The mixture was stirred at ambient temperature overnight. Thesolvent was evaporated under high vacuum and the residue (3.8 g) wasdirectly used in the next step without purification.

f)(N,N′-Bis-tert-butyloxycarbonyl)-{3-[(3-hydroxy-5-methyl)phenoxy)propoxy}guanidine

A mixture of(N,N′-bis-tert-butyloxycarbonyl)-{3-[(benzyloxy-5-methyl)phenoxy]propoxy}guanidine(3.8 g), as prepared in the preceding step, and 10% palladium on carbon(400 mg) in ethanol (30 mL) and THF (30 mL) was stirred under hydrogen(balloon) overnight. The catalyst was removed by filtration throughCelite and the filtrate was concentrated in vacuo. The residue waspurified by flash column chromatography (3:1 ether:hexane) to give thetitle compound as a white foam (2.45 g, 93%). ¹H-NMR (300 MHz, CDCl₃)δ9.09 (s, 1H), 7.74 (br s, 1H), 6.33 (s, 1H), 6.29 (s, 1H), 6.27 (s,1H), 4.20 (t, J=5.9 Hz, 2H), 4.03 (t, J=6.1 Hz, 2H), 2.25 (s, 3H), 2.15(pentet, J=5.9 Hz, 2H), 1.49 (s, 18H).

g) 1,2-Benzenedisulfonic anhydride

A mixture of 1,2-benzenedisulfonic acid dipotassium salt (20 g, 0.064mol) in fuming sulfuric acid (100 mL) was heated at 70-75° C. overnight.The reaction mixture was slowly poured onto ice and the precipitate wasquickly collected by filtration. The solid was treated with benzene (500mL) and dried over anhydrous sodium sulfate. The solvent was filteredand evaporated to give the title compound as a crystalline solid (7.0 g,50% yield), mp 182-3° C. ¹H-NMR (300 MHz, CDCl₃) δ8.02-8.09 (m, 4H).

h)N,N′-(Bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-(2-(4-ethyloxycarbonyl)piperidinylsulfonylphenylsulfonyloxy)phenoxy]propoxy}guanidine

To a solution of 1,2-benzenedisulfonic anhydride (440 mg, 2.0 mmol), asprepared in preceding step, and N,N-diisopropylethylamine (360 μL, 2.0mmol) in dichloromethane (20 mL) was added ethyl isonipecotate (315 mg,2.0 mmol). After stirring the mixture for 4 h at ambient temperature,oxalyl chloride (160 μL, 2.0 mmol) and 5 drops of N,N-dimethylformamidewere added. The mixture was stirred for another 4 h.(N,N′-Bis-tert-butyloxycarbonyl)-{3-[(3-hydroxy-5-methyl)phenoxy)propoxy}guanidine(700 mg, 1.6 mmol), as prepared in step f, and N,N-diisopropylethylamine(360 (L, 2.0 mmol) were added to the mixture. The mixture was stirred atambient temperature overnight and then additional dichloromethane (100mL) was added. The solution was washed with 10% citric acid (3×50 mL)and brine (50 mL), and dried over Na₂SO₄. After the solvent wasevaporated in vacuo, the residue was purified by flash columnchromatography (dichloromethane to 10% ethyl acetate in dichloromethane)to give the title compound as a colorless foam (1.04 g, 81%). ¹H-NMR(300 MHz, CDCl₃) δ9.08 (s, 1H), 8.28 (d, J=7.9 Hz, 1H), 8.15 (d, J=7.8Hz, 1H), 7.78 (t, J=7.7 Hz, 1H), 7.68 (t, J=7.8 Hz, 1H), 7.66 (t, J=7.7Hz, 1H), 6.58 (s, 1H), 6.56 (s, 1H), 6.50 (s, 1H), 4.18 (t, J=6.2 Hz,2H), 4.12 (q, J=7.1 Hz, 2H), 3.94 (t, J=6.2 Hz, 2H), 3.84 (m, 2H), 2.97(t, J=10.3 Hz, 2H), 2.41 (m, 1H), 2.23 (s, 3H), 2.10 (t, J=6.2 Hz, 2H),1.95 (m, 2H), 1.79 (m, 2H), 1.49 (s, 18H), 1.23 (t, J=7.1 Hz, 3H).

i){3-[5-Methyl-3-(2-(4-ethyloxycarbonyl)piperidinylsulfonylphenylsulfonyloxy)phenoxy]propoxy}guanidinehydrochloride

To a solution ofN,N′-(bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-(2-(4-ethyloxycarbonyl)piperidinylsulfonylphenylsulfonyloxy)phenoxy]propoxy}guanidine (270 mg, 0.34 mmol),as prepared in the preceding step, in dichloromethane (10 mL) was addedtrifluoracetic acid (4.0 mL). The mixture was stirred at ambienttemperature for 3 h and the solvent was evaporated in vacuo. The residuewas dissolved in dichloromethane (50 mL), washed with 2 N K₂CO₃ (2×30mL) and dried over Na₂SO₄. After the solvent was evaporated, the residuewas purified by flash column chromatography (10% methanol indichloromethane) and converted to the HCl salt (1 eq. methanolic HCl andconcentration) to give the title compound as a colorless foam (175 mg,85%). ¹H-NMR (300 MHz, DMSO-d₆) 8 8.20 (d, J=7.9 Hz, 1H), 8.15 (d, J=7.9Hz, 1H), 8.01 (t, J=7.7 Hz, 1H), 7.88 (t, J=7.7 Hz, 1H), 6.73 (s, 1H),6.51 (s, 1H), 6.41 (s, 1H), 6.25 (br s, 4H), 4.05 (q, J=7.1 Hz, 2H),3.93 (t, J=6.4 Hz, 2H), 3.76 (m, 2H), 3.71 (t, J=6.1 Hz, 2H), 2.93 (t,J=10.2 Hz, 2H), 2.50 (m, 1H), 2.21 (s, 3H), 1.88 (m, 4H), 1.55 (m, 2H),1.16 (t, J=7.1 Hz, 3H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₂₅H₃₄N₄O₉S₂: 599.2(M+H), 621.2 (M+Na). Found: 599.2, 621.3.

EXAMPLE 212-[5-Methyl-3-(2-(methylsulfonyl)phenylsulfonyloxy)phenoxy]ethoxyguanidine

a)2-[5-Methyl-3-(2-(methylsulfonyl)phenylsulfonyloxy)phenoxy]ethoxytoluene

A solution of 5-methyl-3-[2-(methylsulfonyl)phenylsulfonyloxy]phenol(505 mg, 1.47 mmol), as prepared in step a of Example 8,2-benzyloxyethanol (209 μL, 1.47 mmol), 1,1′-(azodicarbonyl)dipiperidine(444 mg, 1.76 mmol) and anhydrous tetrahydrofuran (10 mL), was cooled to0° C. under nitrogen. Neat tri-N-butylphosphine (0.44 mL, 1.77 mmol) wasadded over 3.5 minutes. The solution was stirred at 0° C. for 1 hour andthen at ambient temperature overnight. Diethyl ether was added and themixture was filtered. The solid was discarded and the filtrate wasconcentrated in vacuo. The product was purified by flash columnchromatography through 40 g of silica gel using 0% to 0.5% diethyl etherin dichloromethane to give the title compound (495 mg, 71%) as acolorless solid. ¹H-NMR (300 MHz, CDCl₃) δ8.44 (dd, 1H, J=7.9, 1.3 Hz),8.10 (dd, 1H, J=7.9, 1.3 Hz), 7.85 (td, 1H, J=7.7, 1.4 Hz), 7.71 (td,1H, J=7.7, 1.4 Hz), 7.28-7.37 (m, 5H), 6.58-6.63 (m, 3H), 4.60 (s, 2H),4.02 (m, 1H), 3.76 (m, 1H), 3.45 (s, 3H), 2.23 (s, 3H). Mass spectrum(MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₂₃H₂₄O₇S₂: 499.1 (M+Na), Found: 498.7.

b) 2-[5-Methyl-3-(2-(methylsulfonyl)phenylsulfonyloxy)phenoxy]ethanol

A mixture of2-[5-methyl-3-(2-(methylsulfonyl)phenylsulfonyloxy)phenoxy]ethoxytoluene(480 mg, 1.01 mmol), as prepared in the preceding step, 10% palladium onactivated carbon (48.2 mg, ethanol (2 mL) and tetrahydrofuran (9 mL) wasstirred at ambient temperature under hydrogen (balloon) for 45 minutes.The mixture was filtered through Celite and the filtrate wasconcentrated to give the title compound (404 mg, quantitative) as acolorless gum. ¹H-NMR (300 MHz, CDCl₃) δ8.45 (dd, 1H, J=7.8, 1.4 Hz),8.13 (dd, 1H, J=7.8, 1.4 Hz), 7.88 (td, 1H, J=7.7, 1.4 Hz), 7.75 (td,1H, J=7.7, 1.4 Hz), 6.60-6.66 (m, 3H), 3.77-3.98 (m, 4H), 2.25 (s, 3H),1.95 (t, 1H, J=6 Hz). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₆H₁₈O₇S₂: 409.0(M+Na). Found: 408.7.

c)2-[5-Methyl-3-(2-(methylsulfonyl)phenylsulfonyloxy)phenoxy]ethoxyguanidine

The title compound was prepared from2-[5-methyl-3-(2-(methylsulfonyl)phenylsulfonyloxy)phenoxy]ethanol (asprepared in the preceding step) in a manner analogous to steps c, d, ande of Example 10. Mass spectrum (MALDI-TOF α-cyano-4-hydroxycinnamic acidmatrix) calcd. for C₁₇H₂₁N₃O₇S₂: 444.1 (M+H), 4.66 (M′Na). Found: 444.5,466.3.

EXAMPLE 222-Hydroxy-3-[5-methyl-3-(2-methylsulfonyl)phenylsulfonyloxyphenoxy]propoxyguanidine

a) 2-Benzyloxy-3[5-methyl-3-(2-methylsulfonyl)phenylsulfonyloxyphenoxy]propanol

A solution of 5-methyl-3-[2-(methylsulfonyl)phenylsulfonyloxy]phenol(2.00 g, 5.85 mmol), as prepared in step a of Example 8,2-benzyloxy-1,3-propanediol (2.0 g, 11.0 mmol), and tri-N-butylphosphine(2.38 g, 9.44 mmol) in tetrahydrofuran (100 mL) at 0° C. was treatedwith dropwise addition of 1,1′-(azodicarbonyl)dipiperidine (2.38 g, 9.44mmol) in tetrahydrofuran (20 mL). The reaction mixture was stirred toambient temperature overnight. The reaction mixture was diluted withdiethyl ether and filtered. The filtrate was concentrated and purifiedby flash chromatography using elutions of 5-10% diethyl ether/methylenechloride to give 1.11 g (38%) of the title compound as colorless oil.¹H-NMR (300 MHz, CDCl₃) δ8.45 (dd, 1H, J=7, 1 Hz), 8.12 (d, 1H, J=7, 1Hz), 7.85 (td, 1H, J=7, 1 Hz), 7.72 (td, 1H, J=7, 1 Hz), 7.28-7.39 (m,5H), 6.60-6.63 (m, 3H), 4.74 (d, 1H, J=12 Hz), 4.64 (d, 1H, J=12 Hz),3.99 (m, 2H), 3.67-3.86 (m, 3H), 3.45 (s, 3H), 2.24 (s, 3H). Massspectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₂₄H₂₆O₈S₂: 5.29 (M+Na). Found: 529.1

b)2-Hydroxy-3-[5-methyl-3-(2-methylsulfonyl)phenylsulfonyloxyphenoxy]propanol

A mixture of2-benzyloxy-3-[5-methyl-3-(2-methylsulfonyl)phenylsulfonyloxyphenoxy]propanol(627 mg, 1.24 mmol), as prepared in the preceding step, 10% palladium onactivate carbon (97.9 mg) and deoxygenated ethanol (20 mL) was stirredat ambient temperature under hydrogen (balloon) for two hours. Themixture was filtered through Celite 545 and the filtrate was evaporated.The product was purified by flash column chromatography through 50 g ofsilica gel using 10% hexane in ethyl acetate to give the title compound(342 mg, 66%) as a colorless resin. ¹H-NMR (300 MHz, CDCl₃) δ8.45 (dd,1H, J=7.8, 1.4 Hz), 8.13 (dd, 1H, J=7.8, 1.4 Hz), 7.88 (td, 1H, J=7.7,1.4 Hz), 7.75 (td, 1H, J=7.7, 1.4 Hz), 7.26 (br s, 2H), 6.65 (br s, 1H),4.03 (complex m, 1H), 3.89-3.97 (m, 2H), 3.80 (dd, 1H, J=11.4, 3.9 Hz),3.70 (dd, 1H, J=11.4, 5.5 Hz), 3.45 (s, 3H), 2.25 (s, 3H). Mass spectrum(MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₇H₂₀O₈S:439.0 (M+Na) Found 438.8.

c)N-[2-Hydroxy-3-[5-methyl-3-(2-methylsulfonyl)phenylsulfonyloxyphenoxy]propoxy]phthalimide

A solution of2-hydroxy-3-[5-methyl-3-(2-methylsulfonyl)phenylsulfonyloxyphenoxy]propanol(461 mg, 1.11 mmol, as prepared in the preceding step),N-hydroxyphthalimide (186 mg, 1.14 mmol),1,1′-(azodicarbonyl)dipiperidine (425 mg, 1.68 mmol) and anhydroustetrahydrofuran (14.7 mL) was cooled to 0° C., and neattri-N-butylphosphine (419 μL, 1.68 mmol) was added dropwise over 3minutes. The reaction was stirred at 0° C. for 5 minutes and then atambient temperature for 3 days. The product was purified by flash columnchromatography through 75 g of silica gel using 60:40 ethylacetate/hexane to give the title compound (209 mg, 33%) as a white foam.Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd.for C₂₅H₂₃NO₁₀S: 584.1 (M+Na), 600.0 (M+K). Found: 583.9, 599.8.

d)2-Hydroxy-3-[5-methyl-3-(2-methylsulfonyl)phenylsulfonyloxyphenoxy]propoxyguanidine

The title compound was prepared fromN-[2-hydroxy-3-[5-methyl-3-(2-methylsulfonyl)phenylsulfonyloxyphenoxy]propoxy]phthalimide(as prepared in the preceding step) in a manner analogous to steps d ande of Example 68. Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamicacid matrix) calcd. for C₁₈H₂₃N₃O₈S₂: 474.1 (M+H), 496.1 (M+Na). Found:473.9, 496.1.

EXAMPLE 233-[3-(2,4-Bis(methylsulfonyl)phenylsulfonyloxy)-5-methylphenoxy]propoxyguanidinehydrochloride

a) 2,4-Bis(methylsulfonyl)benzenesulfonyl chloride

The title compound was prepared in 24% yield from2,4-bis(methylsulfonyl)aniline in a manner analogous to step a ofExample 26. ¹H-NMR (300 MHz, CDCl₃) δ8.91 (d, 1H, J=1.9 Hz), 8.60 (d,1H, J=8.2 Hz), 8.47 (dd, 1H, J=8.2, 1.9 Hz), 3.46 (s, 3H), 3.21 (s, 3H).

b)3-[3-(2,4-Bis(methylsulfonyl)phenylsulfonyloxy)-5-methylphenoxy]propoxyguanidinehydrochloride

The title compound was prepared from2,4-bis(methylsulfonyl)benzenesulfonyl chloride (as prepared in thepreceding step) in a manner analogous to step b of Example 26 and thenstep g of Example 29. Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₉H₂₅N₃O₉S₃: 536.1(M+H), 558.1 (M+Na). Found: 536.2, 558.2.

EXAMPLE 243-[5-Methyl-3-(3-methylsulfonyl)phenylsulfonyloxyphenoxy]propoxyguanidinehydrochloride

a) 3-Methylsulfonylbenzenesulfonyl chloride

The title compound was prepared in 64% yield from3-methylsulfonylylaniline hydrochloride in a manner analogous to step aof Example 26. ¹H-NMR (300 MHz, CDCl₃) δ8.62 (t, 1H, J=2 Hz), 8.35 (m,1H), 8.32 (m, 1H), 7.90 (t, 1H, J=8 Hz), 3.16 (s, 3H).

b)3-[5-Methyl-3-(3-methylsulfonyl)phenylsulfonyloxyphenoxy]propoxyguanidinehydrochloride

The title compound was prepared from 3-methylsulfonylbenzenesulfonylchloride (as prepared in the preceding step) in a manner analogous tostep b of Example 26 and then step g of Example 29. Mass spectrum(MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₁₈H₂₃N₃O₇S₂: 458.1 (M+H). Found: 458.7.

EXAMPLE 253-[3-((2-Chloro-4-methylsulfonyl)phenylsulfonyloxy)-5-methylphenoxy]propoxyguanidinehydrochloride

a) 2-Chloro-4-methylsulfonylbenzenesulfonyl chloride

The title compound was prepared in 51% yield from2-chloro-4-methylsulfonylaniline in a manner analogous to step a ofExample 26. ¹H-NMR (300 MHz, CDCl₃) δ8.37 (d, 1H, J=8.4 Hz), 8.22 (d,1H, J=1.8 Hz), 8.06 (dd, 1H, J=8.4, 1.8 Hz), 3.15 (s, 3H).

b)3-[3-((2-Chloro-4-methylsulfonyl)phenylsulfonyloxy)-5-methylphenoxy]propoxyguanidinehydrochloride

The title compound was prepared from2-chloro-4-methylsulfonylbenzenesulfonyl chloride (as prepared in thepreceding step) in a manner analogous to step b of Example 26 and thenstep g of Example 29. Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd for C₁₈H₂₂ClN₃O₇S₂: 492.1(M+H). Found: 492.2.

EXAMPLE 26(3-(6-(2,3-Dihydro-1,1-dioxobenzo[b]thiophene)phenylsulfonyloxy)-5-methylphenoxy)propoxy]guanidinetrifluoroacetate

a) 1,1-Dioxobenzo[b]thiophene-6-sulfonyl chloride

A mixture of 6-amino-1,1-dioxobenzo[b]thiophene (253 mg, 1.39 mmol) and30% aqueous HCl (1.53 mL) was cooled to 0° C. in an open flask, and then40% aqueous sodium nitrite (754 μL) was added dropwise over 2.25minutes. The mixture was stirred at 0° C. for 15 minutes, and then 30%aqueous HCl (768 μL) and solid CuSO₄ (20.4 mg, 0.128 mmol) were added.To this mixture was added 40% aqueous NaHSO₃ (2.39 mL) dropwise over 6minutes, and the reaction was stirred at 0° C. for 2.5 hours. Thereaction was diluted with water (50 mL) and extracted withdichloromethane (2×50 mL). The combined organic layers were washed withbrine (75 mL), dried over Na₂SO₄, filtered and evaporated. The productwas purified by flash column chromatography through 20 g of silica gelusing CH₂Cl₂ to give the title compound (171 mg, 46%) as a pale yellowsolid. ¹H-NMR (300 MHz, CDCl₃) δ8.35 (m, 1H), 8.26 (dd, 1H, J=8.0, 1.8Hz), 7.65 (d, 1H, J=8.0 Hz), 7.34 (dd, 1H, J=7.0, 1.0 Hz), 7.02 (d, 1H,J=7.0 Hz).

b)N,N′-Bis-tert-butyloxycarbonyl-[(3-(6-(1,1-dioxobenzo[b]thiophene)phenylsulfonyloxy)-5-methylphenoxy)propoxy]guanidine

A solution of(N,N′-bis-tert-butyloxycarbonyl)-[3-((3-hydroxy-5-methyl)phenoxy)propoxy]guanidine(60.0 mg, 0.137 mmol, as prepared in step f of Example 20), CH₂Cl₂ (660μL), N,N-diisopropylethylamine (36 μL, 0.207 mmol), and1,1-dioxobenzo[b]thiophene-6-sulfonyl chloride (36.1 mg, 0.136 mmol, asprepared in the preceding step) was stirred overnight at ambienttemperature. The reaction mixture was concentrated in vacuo, and theresidual gold oil was partitioned between dilute aqueous HCl (10 mL, pH2) and diethyl ether (10 mL). The organic layer was washed with brine(10 mL), dried over Na₂SO₄, filtered and evaporated. The product waspurified by column chromatography through 4.6 g of silica gel using60:40 diethyl ether/hexane to give the title compound (78.7 mg, 86%) asa white semisolid. ¹H-NMR (300 MHz, CDCl₃) δ8.13 (s, 1H), 8.05 (dd, 1H,J=7.9, 1.6 Hz), 7.57 (d, 1H, J=7.9 Hz), 7.34 (dd, 1H, J=7.0, 0.7 Hz),6.95 (d, 1H, J=7.0 Hz), 6.64 (s, 1H), 6.46 (s, 1H), 6.30 (t, 1H, J=2.2Hz), 4.18 (t, 2H, J=6.2 Hz), 3.96 (t, 2H, J=6.2 Hz), 2.27 (s, 3H), 2.11pentet, 2H, J=6.2 Hz), 1.50 (s, 9H), 1.49 (s, 9H). Mass spectrum(MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₂₉H₃₇N₃O₁₁S₂: 468.1 (M-2 t-BOC+3H). Found: 468.2.

c)N,N′-Bis-tert-butyloxycarbonyl-[(3-(6-(2,3-dihydro-1,1-dioxobenzo[b]thiophene)phenylsulfonyloxy)-5-methylphenoxy)propoxy]guanidine

A mixture ofN,N′-bis-tert-butyloxycarbonyl-[(3-(6-(1,1-dioxobenzo[b]thiophene)-phenylsulfonyloxy)-5-methylphenoxy)propoxy]guanidine(8.0 mg, 0.012 mmol, as prepared in the preceding step), deoxygenatedethanol (600 μL), and 10% palladium on activated carbon (1.6 mg) wasstirred at room temperature under hydrogen (balloon) for 1.5 hours. Themixture was filtered through Celite 545, and the filtrate wasconcentrated to give the title compound (6.9 mg, 86%) as a colorlessoil. ¹H-NMR (300 MHz, CDCl₃) δ9.09 (s, 1H), 8.21 (d, 1H, J=1.8 Hz), 8.04(dd, 1H, J=8.1, 1.8 Hz), 7.71 (s, 1H), 7.58 (d, 1H, J=8.0 Hz), 6.63 (brs, 1H), 6.46 (br s, 1H), 6.30 (t, 1H, J=2.2 Hz), 4.18 (t, 2H, J=6.2 Hz),3.96 (t, 2H, J=6.2 Hz), 3.48-3.69 (m, 4H), 2.27 (s, 3H), 2.11 (pentet,2H, J=6.2 Hz), 1.50 (s, 9H), 1.49 (s, 9H).

d)(3-(6-(2,3-Dihydro-1,1-dioxobenzo[b]thiophene)phenylsulfonyloxy)-5-methylphenoxxy)propoxy]guanidinetrifluoroacetate

A solution ofN,N′-bis-tert-butyloxycarbonyl-[(3-(6-(2,3-dihydro-1,1-dioxobenzo[b]thiophene)phenylsulfonyloxy)-5-methylphenoxy)propoxy]guanidine(6.8 mg, 0.010 mmol, as prepared in the preceding step) dichloromethane(150 μL), water (10 μL), and trifluoroacetic acid (150 μL) was stirredat ambient temperature for 1.5 hours. The solution was concentrated invacuo to give the title compound (8.0 mg, quantitative yield) as a lightgold oil. ¹H-NMR (300 MHz, CDCl₃) δ8.16 (dd, 1H, J=8.1, 1.5 Hz), 8.08(br s, 1H), 7.65 (d, 1H, J=8.1 Hz), 6.65 (br s, 1H), 6.60 (br s, 1H),6.24 (br s, 1H), 4.11 (t, 2H, J=5.5 Hz), 4.04 (t, 2H, J=5.5 Hz),3.50-3.66 (m, 4H), 2.30 (s, 3H), 2.09 (pentet, 2H, J=5.5 Hz). Massspectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₁₉H₂₃N₃O₇S₂: 470.1 (M+H), 492.1 (M+Na). Found: 470.1, 492.2.

EXAMPLE 27{3-[5-Methyl-3-(2-(4-carboxyl)piperidinylsulfonylphenylsulfonyloxy)phenoxy]propoxy}guanidine

To a solution of{3-[5-methyl-3-(2-(4-ethyloxycarbonyl)piperidinylsulfonylphenylsulfonyloxy)phenoxy]propoxy}guanidinehydrochloride (90 mg, 0.15 mmol), as prepared in step h of Example 20,in methanol (4.0 mL) was added 2N NaOH (0.2 mL, 0.4 mmol). The mixturewas stirred at ambient temperature for 2 h. The ethyl acetate (3×20 mL).The ethyl acetate solution was washed with brine (20 mL) and dried overNa₂SO₄. After the solvent was evaporated, the residue was purified on aWaters Sep-Pak (10 g silica, 15% methanol in dichloromethane) to givethe title compound as a white solid (50 mg, 58%). ¹H-NMR (300 MHz,DMSO-d₆) δ8.15 (m, 2H), 8.01 (t, J=7.8 Hz, 1H), 7.88 (t, J=7.7 Hz, 1H),6.72 (s, 1H), 6.53 (s, 1H), 6.40 (s, 1H), 5.33 (br s, 4H), 3.93 (t,J=6.4 Hz, 2H), 3.72 (t, J=6.2 Hz, 2H), 3.65 (m, 2H), 2.93 (t, J=10.0 Hz,2H), 2.34 (m, 1H), 2.22 (s, 3H), 1.90 (t, J=6.2 Hz, 2H), 1.86 (m, 2H),1.53 (m, 2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acidmatrix) calcd. for C₂₃H₃₀N₄O₉S₂: 571.2 (M+H), 593.1 (M+Na). Found:571.2, 593.1.

EXAMPLE 283-[5-Methyl-3-(3-methylquinolinyl-8-sulfonyloxy)phenoxy]propoxyguanidinediacetate

a) 3-Methyl-8-quinolinesulfonyl chloride

The title compound was prepared according to the procedure of U.S. Pat.No. 5,332,822. To 9 mL (135 mmol) of chlorosulfonic acid at 0° C. wasadded slowly 3-methylquinoline (5.2 g, 36 mmol). The bath was removedand stirring was continued at 100° C. overnight. The reaction mixturewas cooled to ambient temperature and then treated with 3.3 mL (45 mmol)of thionyl chloride. The reaction mixture was heated at 70° C. for 1 h,cooled to 0° C. and carefully quenched with ice (very vigorousreaction). The reaction mixture was diluted with 100 mL of water andextracted into dichloromethane (100 mL). The organic phase was washedwith water, dried (MgSO₄) and concentrated. The residue was trituratedwith dichloromethane/diethyl ether to provide 1.58 g (18%) of the titlecompound as a tan solid. ¹H-NMR (300 MHz, DMSO-d₆) δ9.17-9.29 (m, 2H),8.32-8.38 (m, 2H), 7.96 (dd, 1H, J=7 Hz), and 2.51 (t, 3H, J=2 Hz).

b) 5-Methyl-3-(3-methylquinolinyl-8-sulfonyloxy)phenol

A mixture of orcinol monohydrate (2.8 g, 19.7 mmol) and3-methyl-8-quinolinesulfonyl chloride (3.68 g, 15.2 mmol), as preparedby the preceding procedure, in diethyl ether (70 mL), tetrahydrofuran(20 mL), and saturated sodium bicarbonate (100 mL) was vigorouslystirred at ambient temperature for 12 h. The reaction mixture wasextracted into 15% tetrahydrofuran/85% dichloromethane, dried (MgSO₄),and purified by flash chromatography using elutions ofdichloromethane/diethyl ether (95:5 to 92:8) to give 1.57 g (31% yield)of the title compound as a colorless solid. ¹H-NMR (300 MHz, DMSO-d₆)δ9.62 (s, 1H), 9.09 (d, 1H, J=1.2 Hz), 8.38-8.34 (m, 2H), 8.27 (dd, 1H,J=7, 1 Hz), 7.72 (t, 1H, J=8 Hz), 6.43 (m, 1H), 6.29 (m, 1H), 6.09 (t,1H, J=2 Hz), 2.58 (s, 3H), 2.09 (s, 3H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₇H₁₅NO₄S: 330.1(M+H), 352.1 (M+Na). Found 329.8, 351.9.

c) 3-[5-Methyl-3-(3-methylquinolinyl-8-sulfonyloxy)phenoxy]propanol

A mixture of 5-methyl-3-(methylquinolinyl-8-sulfonyloxy)phenol (1.73 g,5.26 mmol), as prepared in the preceding step, 3.2 mL (6.4 mmol) of 2 NNaOH, and 540 μL (5.79 mmol) of 3-bromopropanol in 20 mL oftetrahydrofuran was stirred at 50° C. overnight. The reaction mixturewas diluted with water (70 mL), extracted into a 1:1 mixture of ethylacetate/diethyl ether, dried (MgSO₄), and concentrated. The residue wascrystallized from methanol/diethyl ether/hexane to give 1.50 g (74%) ofthe title compound as a colorless powder. ¹H-NMR (300 MHz, DMSO-d₆)δ9.09 (d, 1H, J=2 Hz), 8.26-8.39 (m, 3H), 7.72 (t, 1H, J=7 Hz), 6.63 (s,1H), 6.40 (s, 1H), 6.22 (s, 1H), 4.51 (t, 1H, J=5 Hz), 3.78 (t, 2H, J=7Hz), 3.43 (q, 2H, J=6 Hz), 2.58 (s, 3H), 2.14 (s, 3H), 3.80 (pentet, 2H,J=7 Hz). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acidmatrix) calcd. for C₂₀H₂₁NO₅S: 388.1 (M+H), 410.1 (M+Na). Found: 388.0,409.9.

d)N-[3-[5-Methyl-3-(3-methylquinolinyl-8-sulfonyloxy)phenoxy]propoxy]phthalimide

Diethyl azodicarboxylate (830 μL, 5.3 mmol) was added slowly to3-[5-methyl-3-(3-methylquinolinyl-8-sulfonyloxy)phenoxy]propanol (1.5 g,3.88 mmol), as prepared in the preceding step, N-hydroxyphthalimide (710mg, 4.36 mmol), and triphenylphosphine (1.3 g, 4.96 mmol) in anhydroustetrahydrofuran (70 mL) at 0° C. under a nitrogen atomsphere. Thesolution was stirred at ambient temperature for 90 min. The reactionmixture was diluted with diethyl ether (200 mL), washed with water(2×150 mL), dried (MgSO₄), and concentrated. The residue was dissolvedin dichloromethane and passed through a thick pad of silica gel (100:0to 95:5 dichloromethane/diethyl ether) to give the title compound (2.0g, 82%) as a colorless solid. ¹H-NMR (300 MHz, DMSO-d₆) δ9.11 (s, 1H),8.28-8.38 (m, 3H), 7.72 (t, 1H, J=8 Hz), 6.67 (s, 1H), 6.43 (s, 1H),6.29 (s, 1H), 4.21 (t, 2H, J=7 Hz), 3.96 (t, 2H, J=7 Hz), 2.50 (s, 3H),2.15 (s, 3H), 1,99 (pentet, 2H, J=6 Hz). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₂₈H₂₄N₂O₇S: 533.1(M+H), 555.1 (M+Na). Found 532.9, 554.9.

e) 3-[5-Methyl-3-(quinolinyl-8-sulfonyloxy)phenoxy]propoxyamine

Sodium borohydride (388 mg, 10.3 mmol) was added toN-[3-[5-methyl-3-(3-methylquinolinyl-8-sulfonyloxy)phenoxy]propoxy]phthalimide(2.0 g, 3.17 mmol), as prepared in the preceding step, in ethanol (30mL), tetrahydrofuran (30 mL) and water (10 mL). Hydrogen gas was evolvedfor 40 min. The mixture was stirred overnight at ambient temperature.Aqueous HCl (10 mL, 2N) was added dropwise (hydrogen was evolved), andthe solution was heated at 50° C. for 40 min. The reaction mixture wasconcentrated to ca. ⅓ volume. The reaction mixture was adjusted to pH 10with 2N NaOH, diluted with water and extracted into dichloromethane. Theorganic extracts were washed with water, dried (K₂CO₃), and purified byflash chromatography (85:15 to 67:33 diethyl ether/dichloromethane) togive 1.14 g of the title compound as an oil. ¹H-NMR (300 MHz, CDCl₃)δ9.11 (d, 1H, J=2 Hz), 8.33 (dd, 1H, J=7, 2 Hz), 8.04-8.07 (m, 2H), 7.56(t, 2H, J=8 Hz), 6.53 (s, 1H), 6.46 (s, 1H), 6.41 (s, 1H), 3.84 (t, 2H,J=6 Hz), 3.75 (t, 2H, J=6 Hz), 2.61 (s, 3H, 2.17 (s, 3H), 1.95 (pentent,2H, J=6 Hz). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acidmatrix) calcd. for C₂₀H₂₂N₂O₅S: 403.1 (M+H), 425.1 (M+Na). Found: 403.2,425.1.

f) 3-[5-Methyl-3-(quinolinyl-8-sulfonyloxy)phenoxy]propoxyguanidinediacetate

A solution of3-[5-methyl-3-(3-methylquinolinyl-8-sulfonyloxy)phenoxy]propoxyamine(1.1 g, 2.2 mmol), as prepared in the preceding step, and1H-pyrazole-1-carboxamidine hydrochloride (970 mg, 6.62 mmol) inanhydrous N,N-dimethylformamide (5.0 mL) was stirred at ambienttemperature under nitrogen for 18 h. The solvent was removed in vacuoand acetonitrile was added. The reaction mixture was stirred for 1 h atambient temperature and the resulting pyrazole was removed byfiltration. The filtrate was concentrated and the residue diluted withdichloromethane. The solution was treated with 2 mL of acetic acid andconcentrated. The residue was purified by flash chromatography(93:6.3:0.7 to 89:9.5:1.5 to 78:19:3 dichloromethane/methanol/aceticacid) to give 860 mg (69% yield) of the title compound as a foam. ¹H-NMR(300 MHz, DMSO-d₆) δ9.00 (d, 1H, J=2 Hz), 8.22-8.28 (m, 3H), 7.64 (m,1H), 6.59 (s, 1H), 6.32-6.35 (m, 2H), 3.95 (t, 2H, J=6 Hz), 3.87 (t, 2H,J=6 Hz), 2.61 (s, 3H), 2.11 (s, 3H), 2.01 (pentet, 2H, J=6 Hz). Massspectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₂₁H₂₄N₄O₅S: 445.2 (M+H), 467.1 (M+Na). Found 445:0, 466.9.

EXAMPLE 293-[5-Methyl-3-[2-(N-hydroxy)aminophenylsulfonyloxy]phenoxy]propoxyguanidinehydrochloride

a) 2-(2-Nitrophenylsulfonyloxy)phenol

A mixture of orcinol monohydrate (4.32 g, 30.2 mmol) and2-nitrobenzenesulfonyl chloride (6.65 g, 30.0 mmol) in diethyl ether(100 mL) and saturated NaHCO₃ (100 mL) was stirred at ambienttemperature for 36 h. The reaction mixture was diluted with water (100mL) and extracted into 10% tetrahydrofuran/ethyl acetate, dried (MgSO₄),and concentrated. The residue was diluted with diethyl ether (150 mL)and the resulting disulfonated product (1.6 g) removed by filtration.The filtrate was concentrated and purified by flash chromatography (3:97to 10:90 diethyl ether/dichloromethane) to give 5.67 g (61%) of thetitle compound as an oil. ¹H-NMR (300 MHz, CDCl₃) δ7.99 (dd, 1H, J=7, 2Hz), 7.79-7.86 (m, 2H), 7.65-7.73 (m, 1H), 6.60-6.61 (m, 1H), 6.58-6.59(m, 1H), 6.50-6.51 (m, 1H), 5.32 (s, 1H), 2.25 (s, 3H).

b) 3-[3-(2-Nitrophenylsulfonyloxy)-5-methylphenoxy]propanol

A mixture of 2-(2-nitrophenylsulfonyloxy)phenol (2.0 g, 6.47 mmol), asprepared in the preceding step, 3-bromopropanol (700 μL, 7.5 mmol) and2N NaOH (4 mL, 8 mmol) in tetrahydrofuran (20 mL) was heated at 60° C.for 6 h. The reaction mixture was acidified with 2N HCl, extracted intodichloromethane, dried (MgSO₄), concentrated, and purified by flashchromatography using elutions of 5-20% diethyl ether/dichloromethane togive 1.77 g (74%) of the title compound. ¹H-NMR (300 MHz, CDCl₃) δ7.99(d, 1H, J=7 Hz), 7.80-7.86 (m, 2H), 7.69-7.74 (m, 1H), 6.65 (s, 1H),6.61 (s, 1H), 6.57 (t, 1H, J=2 Hz). 4.03 (t, 2H, J=6 Hz), 3.82 (t, 2H,J=6 Hz), 2.27 (s, 3H), 2.00 pentet, 2H, J=6 Hz).

c)N-[3-[3-(2-Nitrophenylsulfonyloxy)-5-methylphenoxy]propoxy]phthalimide

Diethyl azodicarboxylate (910 μL, 5.78 mmol) was slowly added to asolution of 3-[3-(2-nitrophenylsulfonyloxy)-5-methylphenoxy]propanol(1.77 g, 4.82 mmol), as prepared in the preceding step,triphenylphosphine (1.52 g, 5.80 mmol), and N-hydroxyphthalimide (864mg, 530 mmol) in tetrahydrofuran (10 mL) at 0° C. The reaction mixturewas stirred at room temperature overnight. The reaction mixture wasconcentrated and the product purified by flash chromatography(dichloromethane) to give 2.33 g (95%) of the title compound as an oil.¹H-NMR (300 MHz, CDCl₃) δ7.98 (dd, 1H, J=7, 1 Hz), 7.67-7.88 (m, 7H),6.67 (s, 1H), 6.64 (m, 1H), 6.55 (t, 1H, J=2 Hz), 4.36 (t, 2H, J=6 Hz),4.12 (t, 2H, J=6 Hz), 2.28 (s, 3H), 2.18 (pentet, 2H, J=6 Hz). Massspectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid) calcd. forC₂₄H₂₀N₂O₉S: 535.1 (M+Na). Found 535.0.

d) 3-[3-(2-Nitrophenylsulfonyloxy)-5-methylphenoxy]propoxyamine

A solution ofN-[3-[3-(2-nitrophenylsulfonyloxy)-5-methylphenoxy]propoxy]-phthalimide(2.33 g, 4.55 mmol), as prepared in the preceding step, intetrahydrofuran (30 mL) and ethanol (30 mL) was treated with sodiumborohydride (524 mg, 13.9 mmol). The reaction mixture was stirred atroom temperature overnight, quenched carefully with 2N HCl (14 mL) andheated at 50° C. for 90 min. The reaction mixture was then concentratedto ¼ volume, basified with 2N NaOH, diluted with water, and extractedinto ethyl acetate. The organic phase was dried (K₂CO₃) and purified byflash chromatography (1:4 to 1:2 diethyl ether/dichloromethane to give1.12 g (64%) of the title compound as a pale yellow oil. ¹H-NMR (300MHz, CDCl₃) δ7.98-8.01 (m, 1H), 7.79-7.87 (m, 2H), 7.66-7.74 (m, 1H),6.64 (m, 1H), 6.60 (s, 1H), 6.57 (t, 1H, J=2 Hz), 3.96 (t, 2H, J=6 Hz),3.80 (t, 2H, J=6 Hz), 2.27 (s, 3H), 2.02 (penet, 2H, J=6 Hz). Massspectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid) calcd. forC₁₆H₁₈N₂O₇S: 405.1 (M+Na). Found 405.2.

e)N,N′-(Bis-tert-butyloxycarbonyl)[3-[3-(2-nitrophenylsulfonyloxy)-5-methylphenoxy]propoxy]guanidine

A solution of3-[3-(2-nitrophenylsulfonyloxy)-5-methylphenoxy]propoxyamine (1.12 g,2.93 mmol), as prepared in the previous step, in N,N-dimethylformamide(10 mL) was treated with bis(1,3-t-butyl)-2-methyl-2-thiopseudourea (894mg, 3.08 mmol). The reaction mixture was stirred at 50° C. overnight,then at 65° C. for 24 h. Another 113 mg ofbis(1,3-t-butyl)-2-methyl-2-thiopseudourea was added to the reaction.After stirring at 65° C. for 12 h, the reaction mixture was concentratedand the residue purified by flash chromatography using 3% diethylether/dichloromethane to give 833 mg (46%) of the title compound as oil.¹H-NMR (300 MHz, CDCl₃) δ9.09 (s, 1H), 7.97 (d, 1H), 7.80-7.86 (m, 2H),7.66-7.74 (m, 2H), 6.64 (s, 1H), 6.61 (s, 1H), 6.52 (t, 1H, J=2 Hz),4.18 (t, 2H, J=6 Hz), 3.97 (t, 2H, J=6Hz), 2.27 (s, 3H), 2.11 (pentet,2H, J=6 Hz), 1.49 and 1.50 (two singlets, 18H). Mass spectrum(MALDI-TOF, α-cyano-4-hydroxycinnamic acid) calcd. for C₂₅H₃₆N₄O₁₁S: 447(M−2 t-BOC+3H). Found: 447.

f)N,N′-(Bis-tert-butyloxycarbonyl)-[3-[3-(2-(N-hydroxy)aminophenyl-sulfonyloxy)-5-methylphenoxy]propoxy]guanidine

A solution ofN,N′-(bis-tert-butyloxycarbonyl)-[3-[3-(2-nitrophenylsulfonyloxy)-5-methylphenoxy]propoxy]guanidine(833 mg, 1.3 mmol), as prepare in the preceding step, in tetrahydrofuran(5 mL) containing 10% palladium on carbon (160 mg) was hydrogenated atatmospheric pressure for 3 h. The reaction mixture was filtered throughCelite 545, concentrated, and resubmitted to hydrogenation with freshcatalyst (123 mg) in tetrahydrofuran (5 mL). The reaction still did notconsume the starting material. The reaction mixture was concentrated andthe product was purified by flash chromatography (5 to 10% diethylether/CH₂Cl₂) to give 574 mg (71% yield) of the title compound as afoam. ¹H-NMR (300 MHz, CDCl₃) δ9.05 (s, 1H), 8.37 (s, 1H), 7.69 (s, 1H),7.50-7.61 (m, 4H), 6.89 (t, 1H, J=7 Hz), 6.57 (s, 1H), 6.49 (s, 1H),6.32 (s, 1H), 5.82 (s, 1H), 4.16 (t, 2H, J=6 Hz), 3.90 (t, 2H, J=6 Hz),2.23 (s, 3H), 2.06 (pentet, 2H, J=6 Hz), 1.50 (s, 9H), 1.48 (s, 9H). g)3-[5-Methyl-3-[2-(N-hydroxy)aminophenylsulfonyloxy]phenoxy]propoxyguanidinehydrochloride

A solution ofN,N′-(bis-tert-butyloxycarbonyl)-[3-[3-(2-(N-hydroxy)aminophenyl-sulfonyloxy)-5-methylphenoxy]propoxy]guanidine(85 mg, 0.14 mmol) in dichloromethane (1 mL) was treated with HCl (4N indioxane). The reaction mixture was stirred at ambient temperature for 1h. Additional HCl (300 μL) was added and stirring was continued for 1 h.Another 3 mL of 4N HCl was added. The reaction mixture was stirred for 2h. The reaction mixture was concentrated and suspended in a mixture ofdiethyl ether/dichloromethane/hexane. The solvent was removed in vacuoand the concentration from diethyl ether/dichloromethane/hexane wasrepeated several times to give 74 mg of the title compound as an orangesolid. ¹H-NMR (300 MHz, CD₃OD) δ7.58 (td, 1H, J=7, 1 Hz), 7.40-7.50 (m,2H), 6.80-6.85 (m, 1H), 6.65 (s, 1H), 6.44 (s, 1H), 6.42 (s, 2H),3.95-4.15 (m, 4H), 2.19 (s, 3H), 2.05-2.17 (m, 2H). Mass spectrum(MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₁₇H₂₂N₄O₆S: 411.1 (M+H). Found: 411.0.

EXAMPLE 303-[5-Methyl-3-[2-aminophenylsulfonyloxy]phenoxy]propoxyguanidinehydrochloride

A solution ofN,N′-(bis-tert-butyloxycarbonyl)-[3-[3-(2-(N-hydroxy)aminophenyl-sulfonyloxy)-5-methylphenoxy]propoxy]guanidine(289 mg), as prepared in step f of the preceding Example, intetrahydrofuran (2 mL) containing 10% palladium on carbon washydrogenated at atmospheric pressure for 20 h. The reaction mixture wasfiltered and concentrated. The residue was treated with HCl (1.5 mL; 4Nin dioxane). After stirring for 4 h, the reaction mixture wasconcentrated from dichloromethane/methanol/diethyl ether/hexane to give52 mg (26% yield) of impure title compound. Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₇H₂₂N₄O₅S: 395.1(M+H). Found: 395.2.

EXAMPLE 313-[3-(2-(4-Biphenylmethoxy)phenylsulfonyloxy)-5-methylphenoxy]propoxyguanidine

a) 4-(Bromomethyl)biphenyl

A mixture of 4-phenyltoluene (4.83 g, 28.7 mmol), N-bromosuccinimide(5.64 g, 31.7 mmol), benzoyl peroxide (catalytic), and anhydrous carbontetrachloride (35 mL) was refluxed for 24 hours. The mixture was cooledto room temperature and filtered to give a mixture (7.32 g) of4-(dibromomethyl)biphenyl, 4-(bromomethyl)biphenyl, and 4-phenyltoluene(14:82:4 molar ratio by ¹H-NMR). The product was used without furtherpurification in the next step. ¹H-NMR of the title compound (300 MHz,CDCl₃) δ7.56-7.60 (m, 4H), 7.33-7.48 (m, 5H), 4.55 (s, 2H). Partial¹H-NMR of 4-(dibromomethyl)biphenyl (300 MHz, CDCl₃) δ6.71 (s, 1H).

b) 1-(4-Biphenylmethoxy)-2-iodobenzene

A mixture of 2-iodophenol (6.35 g, 28.8 mmol), acetonitrile (150 mL),cesium carbonate (11.25 g, 3.45 mmol) and 4-(bromomethyl)biphenyl (7.26g, mixture of 4-(dibromomethyl)biphenyl, 4-(bromomethyl)biphenyl and4-phenyltoluene, 14:82:4 molar ratio, as prepared in the preceding step)was stirred at ambient temperature for 1 hour and then concentrated invacuo. The residual solid was partitioned between water (200 mL) andethyl acetate 250 mL). The organic layer was washed with aqueous NaOH(0.1N, 2×200 mL) and brine (200 mL), dried over MgSO₄, filtered andevaporated. The product was purified by flash column chromatographythrough 200 g of silica gel using 0% to 10% dichloromethane in hexane togive the title compound (8.38 g, 76% from 4-phenyltoluene) as a whitesolid. ¹H-NMR (300 MHz, CDCl₃) δ7.81 (dd, 1H, J=7.8, 1.5 Hz), 7.56-7.64(m, 6H), 7.26-7.47 (m, 4H), 6.89 (dd, 1H, J=8.2, 1.2 Hz), 6.74 (td, 1H,J=7.6, 1.2 Hz), 5.20 (s, 2H).

c) 2-(4-Biphenylmethoxy)benzenesulfonyl chloride

A solution 1-(4-biphenylmethoxy)-2-iodobenzene (6.04 g, 15.6 mmol, asprepared in the preceding step) in 40 mL of anhydrous THF was added over45 minutes to a cooled (−78° C.) solution of N-butyllithium (0.89M inhexanes, 14.0 mL, 12.5 mmol) in 75 mL of anhydrous THF. AdditionalN-butyllithium (13 mL, 11.6 mmol) was added to drive the reaction tocompletion. The reaction was stirred at −78° C. for 3 hours, and then acooled (0° C.) solution of SO₂ (18 g, 280 mmol) in 55 mL anhydroustetrahydrofuran was added over 15 minutes. The solution was allowed towarm from −78° C. to 0° C. and then stirred at 0° C. for 30 minutes.Sulfuryl chloride (1.0M in dichloromethane, 72 mL, 72 mmol) was added tothe cooled (0° C.) reaction mixture over 45 minutes. The solution wasstirred at 0° C. for 45 minutes and then at ambient temperatureovernight. The reaction was again cooled to 0° C. and sulfuryl chloride(1.0M in dichloromethane, 47 mL, 47 mmol) was added over 30 minutes. Thesolution was stirred at 0° C. for 30 minutes and then at ambienttemperature for 1 hour. THF was removed by rotary evaporation, and theresidual solution was poured into 1 liter of water and 600 mL of diethylether and separated. The organic layer was washed with water (2×1 L) andbrine (600 mL), dried over MgSO₄, filtered, and evaporated. The productwas chromatographed through 800 g of silica gel using 20% to 35% CH₂Cl₂in hexane. The resulting solid was triturated with hexane and filteredto give the title compound (2.23 g, 40%) as a fluffy white solid. ¹H-NMR(300 MHz, CDCl₃) δ8.16 (dd, 1H, J=8.0, 1.7 Hz), 7.74-7.84 (m, 7H),7.48-7.63 (m, 3H), 7.33 (d, 1H, J=8.5 Hz), 7.27 (t, 1H, J=7.7 Hz), 5.56(s, 2H).

d) [3-(2-(4-Biphenylmethoxy)phenylsulfonyloxy)-5-methylphenyl]acetate

2-(4-Biphenylmethoxy)enzenesulfonyl chloride (3.99 mg, 1.11 mmol, asprepared in the preceding step) was added to a solution of orcinolmonoacetate (185 mg, 1.11 mmol), N,N-diisopropylethylamine (272 μL, 1.56mmol) and dichloromethane (5.6 mL). After stirring overnight at ambienttemperature, the solution was concentrated in vacuo. The residual oilwas partitioned between ethyl acetate (45 mL) and dilute aqueous HCl(0.02N, 45 mL). The organic layer was washed with brine (45 mL), driedover Na₂SO₄, filtered and evaporated to give the title compound (534 mg,98%) as a white solid. ¹H-NMR (300 MHz, CDCl₃) δ7.89 (dd, 1H, J=7.9, 1.7Hz), 7.57-7.64 (m, 7H), 7.32-7.47 (m, 3H), 7.15 (d, 1H, J=8.4 Hz), 7.05(t, 1H, J=7.7 Hz), 6.79 (m, 1H), 6.75 (br s, 1H), 6.66 (m, 1H), 5.33 (s,2H), 2.20 (s, 3H), 2.15 (s, 3H). Mass spectrum (MALDI-TOF, gentisic acidmatrix) calcd. for C₂₈H₂₄O₆S: 511.1 (M+Na). Found: 511.0.

e) 3-(2-(4-Biphenylmethoxy)phenylsulfonyloxy)-5-methylphenol

A mixture of[3-(2-(4-biphenylmethoxy)phenylsulfonyloxy)-5-methylphenyl]acetate (503mg, 1.03 mmol, as prepared in the preceding step), methanol (10 mL),tetrahydrofuran (5 mL) and aqueous NaOH (2N, 0.52 mL) was stirred atambient temperature for 20 minutes and then concentrated in vacuo. Theresidue was partitioned between dilute aqueous HCl and ethyl acetate.The organic layer was washed with brine, dried over Na₂SO₄, filtered andevaporated to give the title compound (468 mg, quantitative yield) as acolorless foam. ¹H-NMR (300 MHz, CDCl₃) δ7.90 (dd, 1H, J=7.9, 1.7 Hz),7.57-7.63 (m, 7H), 7.33-7.47 (m, 3H), 7.16 (d, 1H, J=8.2 Hz), 7.05 (t,1H, J=7.6 Hz), 6.49 (br s, 1H), 6.47 (br s, 1H), 6.30 (t, 1H, J=2.1 Hz),5.35 (s, 2H), 2.15 (s, 3H). Mass spectrum (MALDI-TOF, gentisic acidmatrix) calcd. for C₂₆H₂₂O₅S: 469.1 (M+Na). Found: 469.2

f)3-[3-(2-(4-Biphenylmethoxy)phenylsulfonyloxy)-5-methylphenoxy]propoxyguanidine

The title compound was prepared from3-(2-(4-biphenylmethoxy)phenylsulfonyloxy)-5-methylphenol (as preparedin the preceding step) in a manner analogous to steps b, c, d and e ofExample 10. Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acidmatrix) calcd. for C₃₀H₃₁N₃O₆S: 562.2 (M+H). Found: 562.0.

EXAMPLE 323-[3-(2-(3-Biphenylmethoxy)phenylsulfonyloxy)-5-methylphenoxy]propoxyguanidinehydrochloride

a) 3-(Bromomethyl)biphenyl

The title compound was prepared as a mixture of3-(dibromomethyl)biphenyl, 3-(bromomethyl)biphenyl and 3-phenyltoluenein a 22:69:9 molar ratio (7.77 g from 29.4 mmol of 3-phenyltoluene) in amanner analogous to step a of Example 31. The compound was used withoutpurification in the next step. ¹H-NMR of the title compound (300 MHz,CDCl₃) δ7.33-7.62 (m, 9H), 4.56 (s, 2H).

b) 1-(3-Biphenylmethoxy)-2-iodobenzene

The title compound was prepared in 68% yield (over two steps) in amanner analogous to step b of Example 31. ¹H-NMR (300 MHz, CDCl₃) δ7.81(dd, 1H, J=7.8, 1.6 Hz), 7.77 (br s, 1H), 7.26-7.65 (m, 9H), 6.90 (dd,1H, J=8.2, 1.3 Hz), 6.74 (td, 1H, J=7.6, 1.3 Hz), 5.22 (s, 2H).

c) 2-(3-Biphenylmethoxy)benzenesulfonyl chloride

The title compound, a light yellow oil was prepared in 23% yield in amanner analogous to step of Example 31. ¹H-NMR (300 MHz, CDCl₃) δ8.01(dd, 1H, J=8.0, 1.7 Hz), 7.81 (br s, 1H), 7.33-7.68 (m, 9H), 7.17 (d,1H, J=8.4 Hz), 7.11 (t, 1H, J=7.7 Hz), 5.42 (s, 2H).

d) [3-(2-(3-Biphenylmethoxy)phenylsulfonyloxy)-5-methylphenyl]acetate

The title compound was prepared in 71% yield from2-(3-biphenylmethoxy)benzenesulfonyl chloride in a manner analogous tostep d of Example 31. ¹H-NMR (300 MHz, CDCl₃) δ7.89 (dd, 1H, J=7.9, 1.7Hz), 7.81 (br s, 1H), 7.31-7.63 (m, 9H), 7.14 (d, 1H, J=8.4 Hz), 7.05(t, 1H, J=7.6 Hz), 6.76 (br s, 1H), 6.72 (br s, 1H), 6.64 (t, 1H, J=2.2Hz), 5.35 (s, 2H), 2.18 (s, 3H), 2.14 (s, 3H). Mass spectrum (MALDI-TOF,gentisic acid matrix) calcd. for C₂₈H₂₄O₆S: 511.1 (M+Na). Found: 510.9.

e) 3-(2-(3-Biphenylmethoxy)phenylsulfonyloxy)-5-methylphenol

The title compound was prepared in quantitative yield from[3-(2-(3-biphenylmethoxy)phenylsulfonyloxy)-5-methylphenyl]acetate in amanner analogous to step e of Example 31. ¹H-NMR (300 MHz, CDCl₃) δ7.91(dd, 1H, J=7.9, 1.7 Hz), 7.85 (br s, 1H), 7.32-7.63 (m, 9H), 7.16 (d,1H, J=8.3 Hz), 7.05 (t, 1H, J=7.8 Hz), 6.48 (br,s 1H), 6.43 (br s, 1H),6.25 (t, 1H, J=2.2 Hz), 5.36 (s, 2H), 2.11 (s, 3H). Mass spectrum(MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₂₆H₂₂O₅S:469.1 (M+Na). Found: 469.1.

f)3-[3-(2-(3-Biphenylmethoxy)phenylsulfonyloxy)-5-methylphenoxy]propoxyguanidinehydrochloride

The title compound was prepared from 3-(2-(3-biphenylmethoxy)phenylsulfonyloxy)-5-methylphenol (as prepared in the preceding step) ina manner analogous to steps b, c, d and e of Example 10. Mass spectrum(MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₃₀H₃₁N₃O₆S: 562.2 (M+H), 584.2 (M+Na). Found 561.9, 584.0.

EXAMPLE 331-[(3-Benzyloxy-5-methylphenoxy)methyl]-1,1-cyclopropylethoxyguanidine

a) 1-[(3-Benzyloxy-5-methylphenoxy)methyl]-1,1-cyclopropylethanol

The title compound was prepared in 72% yield from3-benzyloxy-5-methylphenol, as prepared in step a of Example 20, in amanner analogous to step b of Example 11. ¹H-NMR (300 MHz, CDCl₃)δ7.34-7.44 (m, 5H), 6.43 (s, 1H), 6.37 (s, 1H), 6.36 (s, 1H), 5.02 (s,2H), 3.89 (s, 2H), 3.63 (s, 2H), 2.29 (s, 3H), 0.63 (s, 4H).

b)N-{1-[(3-Benzyloxy-5-methylphenoxy)methyl]-1,1-cyclopropylethoxy}phthalimide

The title compound was prepared in 72% yield from1-[(3-benzyloxy-5-methylphenoxy)methyl]-1,1-cyclopropylethanol, asprepared in the preceding step, in a manner analogous to step a ofExample 11. ¹H-NMR (300 MHz, CDCl₃) δ7.81 (m, 2H), 7.73 (m, 2H),7.31-7.45 (m, 5H), 6.44 (s, 1H), 6.43 (s, 1H), 6.41 (s, 1H), 5.03 (s,2H), 4.23 (s, 2H), 4.09 (s, 2H), 2.29 (s, 3H), 0.71 (m, 4H).

c) 1-[(3-Benzyloxy-5-methylphenoxy)methyl]-1,1-cyclopropylethoxyamine

A solution ofN-{1-[(3-benzyloxy-5-methylphenoxy)methyl]-1,1-cyclopropylethoxy}phthalimide(419 mg, 0.945 mmol, as prepared in the preceding step), tetrahydrofuran(3.5 mL), ethanol (25 mL), and 40% aqueous methylamine (0.81 mL, 9.45mmol) was stirred at ambient temperature for 1 hour and thenconcentrated in vacuo. After stirring the residue with 15 mL of 8:2ethyl acetate/hexane, the mixture was filtered and the filtrate wasconcentrated. The product was purified by flash column chromatography(1:1 ethyl acetate/hexane) to give the title compound (271 mg, 92%) as acolorless liquid. ¹H-NMR (300 MHz, CDCl₃) δ7.32-7.45 (m, 5H), 6.41 (brs, 1H), 6.39 (t, 1H, J=2.2 Hz), 6.37 (br s, 1H), 5.44 (br s, 1H), 5.02(s, 2H), 3.84 (s, 2H), 3.69 (s, 2H), 2.29 (s, 3H), 0.64 (s, 4H). Massspectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₁₉H₂₃NO₃: 314.2 (M+H), 336.2 (M+Na). Found 314.3, 336.3.

d)1-[(3-Benzyloxy-5-methylphenoxy)methyl]-1,1-cyclopropylethoxyguanidine

A solution of1-[(3-benzyloxy-5-methylphenoxy)methyl]-1,1-cyclopropylethoxyamine (245mg, 0.782 mmol), as prepared in the preceding step,1H-pyrazole-1-carboxamidine hydrochloride (228 mg, 1.56 mmol) andN,N-dimethylformamide (5 mL) was stirred overnight at ambienttemperature. The reaction mixture was concentrated in vacuo, and theresidual colorless oil was dissolved in acetonitrile (5 mL). The mixturewas filtered, the collected solid was discarded, and the filtrate wasconcentrated. The crude product was partitioned between dilute aqueousHCl (15 mL, pH 2) and diethyl ether (10 mL). The aqueous layer wasextracted again with diethyl ether (10 mL), and the ether layers werediscarded. The aqueous layer was neutralized (pH 6-7) with 2N aqueousNaOH and extracted with ethyl acetate (2×25 mL). The combined ethylacetate layers were washed with brine, dried over Na₂SO₄, filtered andevaporated. The product was purified by flash column chromatography (7%to 10% methanol in dichloromethane) to give the title compound (123 mg,44%) as a white solid. ¹H-NMR (300 MHz, CD₃OD) δ7.26-7.43 (m, 5H), 6.41(br s, 1H), 6.35 (br s, 1H), 5.01 (s, 2H), 3.89 (s, 2H), 3.77 (s, 2H),2.25 (s, 3H), 0.64 (s, 4H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₂₀H₂₅N₃O₃: 356.2(M+H), 378.2 (M+Na). Found 356.1, 378.1.

EXAMPLE 34{3-[5-Methyl-3-bis(2-methoxyethyl)aminosulfonylphenylsulfonyloxy)phenoxy]propoxy}guanidinehydrochloride

a)N,N′-(Bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-bis(2-methoxyethyl)aminosulfonylphenylsulfonyloxy)phenoxy]propoxyguanidine

The title compound was prepared in 29% yield frombis(2-methoxyethyl)amine in a manner analogous to step h of Example 20.¹H-NMR (300 MHz, CDCl₃) δ9.05 (s, 1H), 8.28 (dd, J=4.9, 1.3 Hz, 1H),8.10 (dd, J=7.9, 1.4 Hz, 1H), 7.58-7.76 (m, 3H), 6.51-6.57 (m, 3H), 4.15(t, J=6.2 Hz, 2H), 3.91 (t, J=6.2 Hz, 2H), 3.65 (t, J=5.6 Hz, 2H), 3.50(t, J=5.7 Hz, 2H), 3.24 (s, 3H), 2.22 (s, 3H), 2.07 (pentet, 2H, J=6Hz), 1.47 (s, 18H).

b){3-[5-Methyl-3-bis(2-methoxyethyl)aminosulfonylphenylsulfonyloxy)phenoxy]propoxy}guanidinehydrochloride

The title compound was prepared in 87% yield fromN,N′-(bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-bis(2-methoxyethyl)aminosulfonylphenylsulfonyloxy)phenoxy]propoxy}guanidine, as prepared in thepreceding step, in a manner analogous to step i of Example 20. ¹H-NMR(300 MHz, CDCl₃) δ8.24 (d, J=6.6 Hz, 1H), 8.18 (d, J=7.6 Hz, 1H),7.69-7.79 (m, 2H), 6.64 (br s, 1H), 659 (br s, 2H), 4.08 (m, 2H), 4.00(m, 2H), 3.65 (br s, 4H), 3.52 (br, s 4H), 3.27 (s, 6H), 2.25 (s, 3H),2.09 (m, 2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acidmatrix) calcd. for C₂₃H₃₄N₄O₉S₂: 575.2 (M+H), 597.2 (M+Na). Found:575.1, 597.3.

EXAMPLE 35{3-[5-Methyl-3-(N-ethyl-3,4-(methylenedioxy)anilinosulfonylphenylsulfonyloxy)phenoxy]propoxy}guanidinehydrochloride

a)N,N′-(Bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-(N-ethyl-3,4-(methylenedioxy)anilinosulfonylphenylsulfonyloxy)phenoxy]propoxy}guanidine

The title compound was prepared in 35% yield fromN-ethyl-3,4-(methylenedioxy)aniline in a manner analogous to step h ofExample 20. ¹H-NMR (300 MHz, CDCl₃) δ9.07 (s, 1H), 8.09-8.14 (m, 1H),7.83-7.88 (m, 1H), 7.71 (s, 1H), 7.52-7.61 (m, 2H), 6.71 (d, J=1.8 Hz,1H), 6.56-6.66 (m, 5H), 5.95 (s, 2H), 4.12 (q, J=7.0 Hz, 4H), 3.94 (q,J=6.9 Hz, 4H), 2.26 (s, 3H), 2.09 (pentet, 2H, J=6 Hz), 1,49 (s, 18H),1.16 (t, J=7.1 Hz, 3H).

b){3-[5-Methyl-3-(N-ethyl-3,4-(methylenedioxy)anilinosulfonylphenylsulfonyloxy)phenoxy]propoxy}guanidinehydrochloride

The title compound was prepared in 61% yield fromN,N′-(bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-(N-ethyl-3,4-(methylenedioxy)anilinosulfonylphenylsulfonyloxy)phenoxy]propoxy}guanidine,as prepared in the preceding step, in a manner analogous to step i ofExample 20. ¹H-NMR (300 MHz, CDCl₃) δ10.82 (s 1H), 8.13 (m, 1H), 7.87(m, 1H), 7.61 (m, 2H), 6.56-6.69 (m, 6H), 5.95 (s, 2H), 3.85-4.07 (m,6H), 2.23 (s, 3H), 2.08 (m, 2H), 1.14 (t, J=7.1 Hz, 3H). Mass spectrum(MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₂₆H₃₀N₄O₉S₂: 607.2 (M+H), 629.1 (M+Na). Found: 607.0, 629.1.

EXAMPLE 36{3-[5-Methyl-3-(2-N-methyl-(3,4-dimethoxyphenyl)ethylaminosulfonylphenylsulfonyloxy)phenoxy]propoxy}guanidinehydrochloride

a)N,N′-(Bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-(2-N-methyl-(3,4-dimethoxyphenyl)ethylaminosulfonylphenylsulfonyloxy)phenoxy]propoxy}guanidine

The title compound was prepared in 46% yield fromN-methylhomoveratrylamine in a manner analogous to step h of Example 20.

b){3-[5-Methyl-3-(2-N-methyl-(3,4-dimethoxyphenyl)ethylaminosulfonylphenylsulfonyloxy)phenoxy]propoxy}guanidinehydrochloride

The title compound was prepared in 63% yield fromN,N′-(bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-(2-N-methyl-(3,4-dimethoxyphenyl)ethylaminosulfonylphenylsulfonyloxy)phenoxy]propoxy}guanidine,as prepared in the preceding step, in a manner analogous to step i ofExample 20. ¹H-NMR (300 MHz, CDCl₃) δ10.85 (s, 1H), 8.11 (m, 2H), 7.75(t, J=7.0 Hz, 1H), 7.66 (t, J=7.5 Hz, 1H), 6.53-6.76 (m, 6H), 4.06 (t,J=5.4 Hz, 2H), 3.96 (t, J=5.5 Hz, 2H), 3.83 (s, 6H), 3.55 (t, J=7.5 Hz,2H), 2.97 (s, 3H), 2.84 (t, J=7.0 Hz, 2H), 2.23 (s, 3H), 2.06 (m, 2H).Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd.for C₂₈H₃₆N₄O₉S₂: 637.2 (M+H), 659.2 (M+Na). Found: 637.3, 659.5.

EXAMPLE 37{3-[5-Methyl-3-((3-ethoxycarbonyl-1-piperidinosulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidinehydrochloride

a)N,N′-(Bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-((3-ethoxycarbonyl-1-piperidinosulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidine

The title compound was prepared in 51% yield from ethyl nipecotate in amanner analogous to step h of Example 20. Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₃₅H₅₀N₄O₁₃S₂: 599.3(M -2 t-BOC+3H). Found: 599.5.

b){3-[5-Methyl-3-((3-ethoxycarbonyl-1-piperidinosulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidine hydrochloride

The title compound was prepared in 63% yield fromN,N′-(bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-((3-ethoxycarbonyl-1-piperidinosulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidine,as prepared in the preceding step, in a manner analogous to step i ofExample 20. ¹H-NMR (300 MHz, CDCl₃) δ10.84 (s, 1H), 8.22 (dd, J=7.9, 1.3Hz, 1H), 8.15 (dd, J=7.9, 1.3 Hz, 1H), 7.80 (td, J=7.7, 1.3 Hz, 1H),7.68 (td, J=7.7, 1.3 Hz, 1H), 6.57 (m, 1H), 6.51 (m, 2H), 4.03-4.12 (m,4H), 3.90-3.97 (m, 3H), 3.75 (m, 1H), 2.97-3.05 (m, 1H), 2.83-2.90 (m,1H), 2.57-2.66 (m, 1H), 2.22 (s, 3H), 2.02-2.14 (m, 3H), 1.48-1.79 (m,3H), 1.21 (t, J=7.0 Hz, 3H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₂₅H₃₄N₄O₉S₂: 599.2(M+H), 621.2 (M+Na). Found: 599.0, 620.9.

EXAMPLE 38{3-[5-Methyl-3-((3-carboxypiperidinosulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidinehydrochloride

A solution of{3-[5-methyl-3-((3-ethoxycarbonyl-1-piperidinosulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidinehydrochloride (0.056 g, 0.09 mmol), as prepared in the preceding step,in methanol (3 mL) and 0.25N NaOH (1.5 mL) was stirred at ambienttemperature for 2 h. The methanol was evaporated. The concentrate wasdiluted with water, washed with dichloromethane and adjusted to pH 7with 10% HCl. The aqueous layer was extracted with ethyl acetate (4×10mL). The ethyl acetate extracts were combined, washed with brine, dried(Na₂SO₄), and evaporated to dryness to give the title compound as awhite solid (0.035 g, 69% yield). ¹H-NMR (300 MHz, CDCl₃/DMSO-d₆) δ8.07(dd, J=7.9, 1.1 Hz, 1H), 8.00 (dd, J=7.9, 1.3 Hz, 1H), 7.81 (td, J=7.7,1.4 Hz, 1H), 7.65 (td, J=7.7, 1.2 Hz, 1H), 6.79 (s, 1H), 6.60 (s, 1H),6.30 (t, J=2.0 Hz, 1H), 3.92-4.02 (m, 5H), 3.73-3.84 (m, 1H), 2.94-3.04(m, 2H), 2.40-2.47 (m, 1H), 2.33 (s, 3H), 1.85-2.16 (m, 4H), 1.51-1.73(m, 2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acidmatrix) calcd. for C₂₃H₃₀N₄O₉S₂: 571.2 (M+H), 593.1 (M+Na). Found:571.2, 593.3.

EXAMPLE 39{3-[5-Methyl-3-((2-methoxycarbonyl1-pyrrolidinosulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidinehydrochloride

a)N,N′-(Bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-((2-methoxycarbonyl-1-pyrrolidinosulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidine

The title compound was prepared in 35% yield from L-proline methyl esterhydrochloride in a manner analogous to step h of Example 20. ¹H-NMR (300MHz, CDCl₃) δ9.05 (s, 1), 8.36 (dd, J=7.9, 1.3 Hz, 1H), 8.11 (dd, J=7.9,1.3 Hz, 1H), 7.76 (td, J=7.6, 1.3 Hz, 1H), 7.60-7.68 (m, 2H), 6.51-6.56(m, 3H), 4.79 (dd, J=8.3, 2.8 Hz, 1H), 4.15 (t, J=6.2 Hz, 2H), 3.91 (td,J=6.2, 1.3 Hz, 2H), 3.62 (s, 3H), 2.2-2.30 (m, 4H), 1.91-2.17 (m, 7H),1.47 (s, 18H), 1.24 (t, J=7.1 Hz, 2H).

b){3-[5-Methyl-3-((2-methoxycarbonyl-1-pyrrolidinosulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidinehydrochloride

The title compound was prepared in 45% yield fromN,N′-(bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-((2-methoxycarbonyl-1-pyrrolidinosulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidine,as prepared in the preceding step, in a manner analogous step i ofExample 20. ¹H-NMR (300 MHz, CDCl₃) δ8.35 (dd, J=7.9, 1.3 Hz, 1), 8.19(dd, J=7.9, 1.3 Hz, 1H), 7.84 (td, J=7.7, 1.3 Hz, 1H), 7.71 (td, J=7.7,1.3 Hz, 1H), 6.57-6.66 (m, 1H), 4.78 (dd, J=8.3, 2.6 Hz, 1H), 4.08 (t,J==5.8 Hz, 2H), 3.99 (t, J=5.8 Hz, 2H), 3.60-3.66 (m, 4H), 3.42 (m, 1H),2.25 (s, 3H), 1.91-2.20 (m, 4H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₂₃H₃₀N₄O₉S₂: 571.2(M+H), 593.1 (M+Na). Found: 571.0, 593.3.

EXAMPLE 40{3-[5-Methyl-3-((2-carboxy-1-pyrrolidinosulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidinehydrochloride

A solution of{3-[5-methyl-3-((2-carboxy-1-pyrrolidinosulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidinehydrochloride (0.037 g, 0.065 mmol), as prepared in the preceding step,in methanol (3 mL) and 0.25 NaOH (1.0 mL) was stirred at ambienttemperature for 2 h. The methanol was evaporated. The concentrate wasdiluted with water, washed with dichloromethane, and adjusted to pH 7with 10% HCl. The aqueous was extracted with ethyl acetate (4×10 mL).The ethyl acetate extracts were combined, washed with brine, dried, andevaporated to dryness to give the title compound as a white solid (0.015g, 43% yield). ¹H-NMR (300 MHz, CDCl₃/DMSO-d₆) δ8.41 (d, J=7.0 Hz, 1H),8.05 (dd, J=7.8, 1.0 Hz, 1H), 7.79 (td, J=7.7, 1.2 Hz, 1H), 7.64 (t,1H), 6.72 (s, 1H), 6.60 (s, 1H), 6.49 (s, 1H), 4.60 (dd, J=7.7, 2.9 Hz,1H), 3.88-4.03 (m, 4H), 3.54-3.67 (m, 2H), 2.30 (s, 3H), 1.94-2.27 (m,6H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix)calcd. for C₂₂H₂₈N₄O₉S₂: 557.1 (M+H), 579.1 (M+Na). Found: 557.0, 579.0.

EXAMPLE 41{3-[5-Methyl-3-(N-methyl-N-ethoxycarbonylmethyl)aminosulfonylphenylsulfonyloxy)phenoxy]propoxy}guanidinehydrochloride

a)N,N′-(Bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-(N-methyl-N-ethoxycarbonylmethyl)aminosulfonylphenylsulfonyloxy)phenoxy]propoxy}guanidine

The title compound was prepared in 67% yield from sarcosine ethyl esterhydrochloride in a manner analogous to step h of Example 20. ¹H-NMR (300MHz, CDCl₃) δ9.08 (s, 1H), 8.37 (dd, J 7.9, 1.3 Hz, 1H), 8.14 (dd,J=7.9, 1.3 Hz, 1H), 7.81 (dt, J=7.7, 1.4 Hz, 1H), 7.64-7.73 (m, 2H),6.51-6.59 (m, 3H), 4.09-4.20 (m, 4H), 3.94 (t, J=6.2 Hz, 2H), 2.99 (s,3H), 2.26 (s, 3H), 2.06-2.15 (m, 2H), 1.49 (s, 18H), 1.20-1.28 (m, 5H).

b){3-[5-Methyl-3-(N-methyl-N-ethoxycarbonylmethyl)aminosulfonylphenylsulfonyloxy)phenoxy]propoxy}guanidinehydrochloride

The title compound was prepared in 72% yield fromN,N′-(Bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-(N-methyl-N-ethoxycarbonylmethyl)aminosulfonylphenylsulfonyloxy)phenoxy]propoxy}guanidine, as prepared in the preceding step, in amanner analogous to step i of Example 20. ¹H-NMR (300 MHz, CDCl₃) δ8.34(dd, J=7.9, 1.3 Hz, 1H), 8.18 (dd, J=7.9, 1.3 Hz, 1H), 7.85 (td, J=7.7,1.3 Hz, 1H), 7.71 (td, J=7.7, 1.3 Hz, 1H), 6.64 (s, 1H), 6.59 (s, 1H),6.54 (t, J=2.0 Hz, 1H), 4.27 (s, 2H), 4.06-4.17 (m, 4H), 3.98 (t, J=5.7Hz, 2H), 2.99 (s, 3H), 2.25 (s, 3H), 2.06-2.17 (m, 2H), 1.22 (t, J=7.2Hz, 3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acidmatrix) calcd. for C₂₂H₃₀N₄O₉S₂: 559.2 (M+H), 581.1 (M+Na). Found:559.2, 581.2.

EXAMPLE 42{3-[5-Methyl-3-(N-methyl-N-ethoxycarbonylmethyl)aminosulfonylphenylsulfonyloxy)phenoxy]propoxy}guanidinehydrochloride

A solution of{3-[5-methyl-3-(N-methyl-N-ethoxycarbonylmethyl)aminosulfonylphenylsulfonyloxy)phenoxy]propoxy}guanidinehydrochloride (0.076 g, 0.136 mmol), as prepared in the preceding step,in methanol (3 mL) and 0.25N NaOH (1.5 mL) was stirred at ambienttemperature for 2 h. The methanol was evaporated. The concentrate wasdiluted with water, washed with dichloromethane, and adjusted to pH 7with 10% HCl. The aqueous was extracted with ethyl acetate (4×10 mL).The ethyl acetate extracts were combined, washed with brine, dried, andevaporated to dryness to give the title compound as a white solid (0.055g, 76% yield). ¹H-NMR (300 MHz, DMSO-d₆) δ8.26 (dd, J=7.9, 1.3 Hz, 1H),8.11 (dd, J=7.9, 1.3 Hz, 1H), 7.99 (td, J=7.7, 1.2 Hz, 1H), 7.85 (td,J=7.7, 1.2 Hz, 1H), 6.74 (m, 1 H), 6.47-6.56 (m, 2H), 4.13 (s, 2H), 3.97(t, J=6.2 Hz, 2H), 3.89 (t, J=6.2 Hz, 2H), 3.34 (s, 3H), 2.22 (s, 3H),1.96-2.02 (m, 2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamicacid matrix) calcd. for C₂₀H₂₆N₄O₉S₂: 531.1 (M+H), 553.1 (M+Na). Found:531.3, 553.3.

EXAMPLE 433-[5-Methyl-3-(2-(4-methylsulfonylpiperazin-1-ylsulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidinehydrochloride

a)N,N′-(Bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-(2-(4-methylsulfonylpiperazin-1ylsulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidinehydrochloride

To a solution of 1,2-benzenedisulfonic anhydride (440 mg, 2.0 mmol), asprepared in step g of Example 20, and N,N-diisopropylethylamine (720 (L,4.0 mmol) in dichloromethane (20 mL) was added(N-methylsulfonyl)piperazine hydrochloride (400 mg, 2.0 mmol). Afterstirring the mixture for 4 h at ambient temperature, oxalyl chloride(160 (L, 2.0 mmol) and 5 drops of N,N-dimethylformamide were added. Themixture was stirred for another 4 h.(N,N′-bis-tert-butyloxycarbonyl)-{3-[(3-hydroxy-5-methyl)phenoxy)propoxy}guanidine(560 mg, 1.4 mmol), as prepared in step f of Example 20, andN,N-diisopropylethylamine (360 (L, 2.0 mmol) were added to the mixture.The mixture was stirred at ambient temperature overnight. Additionaldichloromethane (100 mL) was added and the solution was washed with 10%citric acid (3×50 mL), brine (50 mL), and dried over Na₂SO₄. After thesolvent was evaporated n vacuo, the residue was purified by flash columnchromatography (dichloromethane to 5% ethyl acetate in dichloromethane)to give the title compound as a colorless foam (1.0 g, 89%). ¹H-NMR (300MHz, CDCl₃) δ9.08 (s, 1H), 8.31 (d, J=7.9 Hz 1H), 8.18 (d, J=7.9Hz, 1H),7.82 (t, J=7.8 Hz, 1H), 7.72 (t, J=7.7 Hz, 2H), 6.60 (s, 1H), 6.54 (s,1H), 6.48 (s, 1H), 4.18 (t, J=6.1 Hz, 2H), 3.95 (t, J=6.2 Hz, 2H), 3.52(m, 4), 3.31 (m, 4H), 2.78 (s, 3H), 2.24 (s, 3H), 2.11 (t, J=6.2 Hz,2H), 1.49 (s, 18H).

b)3-[5-Methyl-3-(2-(4-methylsulfonylpiperazin-1-ylsulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidinehydrochloride

To a solution ofN,N′-(bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-(2-(4-methylsulfonylpiperazin-1-ylsulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidine(725 mg, 0.9 mmol), as prepared in the preceding step, indichloromethane (20 mL) was added trifluoracetic acid (5 mL). Themixture was stirred at ambient temperature for 3 h, the solvent wasevaporated in vacuo. The residue was dissolved in dichloromethane (100mL), washed with 2N K₂CO₃ (2×50 mL) and dried over Na₂SO₄. Afterevaporated the solvent, the residue was converted to the HCl salt (1 eq.methanolic HCl and concentration) and purified by flash columnchromatography (10% methanol in dichloromethane) to give the titlecompound as a colorless foam (530 mg, 91%). ¹H-NMR (300 MHz, DMSO-d₆)δ10.97 (br s, 1H), 8.22 (d, J=7.9 Hz, 1H), 8.17 (d, J=7.9 Hz, 1H), 8.03(t, J=7.7 Hz, 1H), 7.91 (t, J=7.7 Hz, 2H), 7.23 (br s, 4H), 6.75 (s,1H), 6.52 (s, 1H), 6.49 (s, 1H), 3.98 (t, J=6.3 Hz, 2H), 3.88 (t, J=6.3Hz, 2H), 3.42 (m, 4H), 3.20 (m, 4H), 2.91 (s, 3H), 2.22 (s, 3H), 2.00(pentet, J=6.3 Hz, 2H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₂₂H₃₁N₅O₉S₃: 606.1(M+H), 628.1 (M+Na). Found: 605.9, 628.1.

EXAMPLE 44{3-[5-Methyl-3-(2-(4-(2-pyrimidinyl)piperazin-1-ylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride

a)N,N′-(Bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-(2-(4-(2-pyrimidinyl)piperazin-1-ylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine}hydrochloride

To a solution of 1,2-benzenedisulfonic anhydride (110 mg, 0.5 mmol), asprepared in step g of Example 20, and N,N-diisopropylethylamine (90 (L,0.5 mmol) in dichloromethane (10 mL) was added2-(1-piperazinyl)pyrimidine (82 mg, 0.5 mmol). After stirring themixture for 4 h at ambient temperature, oxalyl chloride (40 (L, 0.5mmol) and 2 drops of N,N-dimethylformamide were added. The mixture wasstirred for another 4 h.(N,N′-Bis-tert-butyloxycarbonyl)-{3-[(3-hydroxy-5-methyl)phenoxy)propoxy}guanidine(180 mg, 0.4 mmol), as prepared in step f of Example 20, andN,N-diisopropylethylamine (180 (L, 1.0 mmol) were added to the mixture.The mixture was stirred at ambient temperature overnight. Additionaldichloromethane (50 mL) was added, washed with 10% citric acid (3×20 mL)and brine (20 mL), and dried over Na₂SO₄. After the solvent wasevaporated in vacuo, the residue was purified on a Waters Sep-Pak (5 gsilica, 3:1 hexane:ethyl acetate) to give the title compound as acolorless foam (185 mg, 64%). ¹H-NMR (300 MHz, CDCl₃) δ9.08 (s, 1H),8.29 (d, J=4.8 Hz, 1H),8.17 (d, J=8.0 Hz, 1H), 7.81 (t, J=7.7 Hz, 1H),7.70 (m, 2H), 6.59 (s, 1H), 6.57 (s, 1H), 6.52 (s, 1H), 6.49 (s, 1H),4.18 (t, J=6.2 Hz, 2H), 3.93 (m, 6H), 3.43 (m, 4H), 2.24 (s, 3H), 2.10(pentet, J=6.2 Hz, 2H), 1.49 (s, 18H).

b)3-[5-Methyl-3-(2-(4-(2-pyrimidinyl)piperazin-1-ylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride

To a solution ofN,N′-(bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-(2-(4-(2-pyrimidinyl)piperazin-1-ylsulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidine (170 mg, 0.235 mmol), as preparedin the preceding step, in dichloromethane (6 mL) was addedtrifluoroacetic acid (3 mL). The mixture was stirred at ambienttemperature for 2 h, the solvent was evaporated in vacuo. The residuewas dissolved in dichloromethane (50 mL), washed with 2N K₂CO₃ (2×30 mL)and dried over Na₂SO₄. After evaporated the solvent, the residue wasconverted to the HCl salt by HCl methanol to give the title compound asa colorless foam (140 mg, 93%). ¹H-NMR (300 MHz, DMSO-d₆) δ11.09 (s,1H), 8.38 (d, J=5.0 Hz, 2H), 8.16-8.24 (m, 2H), 8.01 (t, J=7.7 Hz, 1H),7.90 (t, J=7.7 Hz, 2H), 7.69 (br s, 4H), 6.74 (s, 1H), 6.68 (t, J=4.8Hz, 1H), 6.54 (s, 1H), 6.51 (s, 1H), 3.99 (t, J=6.2 Hz, 2H), 3.90 (t,J=6.3 Hz, 2H), 3.83 (m, 4H), 3.36 (m, 4H), 2.22 (s, 3H), 2.01 (pentet,J=6.3 Hz, 2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acidmatrix) calcd. for C₂₅H₃₁N₇O₇S₂: 606.2 (M+H), 628.2 (M+Na). Found:606.0, 627.9.

EXAMPLE 453-[5-Methyl-3-(2-(N-methyl-N-(2-(2-pyridyl)ethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinedihydrochloride

a)N,N′-(Bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-(2-(N-methyl-N-(2-(2-pyridyl)ethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidine

The title compound was prepared in 67% yield from2-(2-methylaminoethyl)pyridine in a manner analogous to step h ofExample 20. ¹H-NMR (300 MHz, CDCl₃) δ9.08 (s, 1H), 8.44 (d, J=4.9 Hz,1H), 8.21 (d, J=7.9 Hz, 1H), 8.10 (d, J=7.9 Hz, 1H), 7.77 (d, J=7.7 Hz,1H), 7.72 (d, J=7.7 Hz, 1H), 7.62 (t, J=7.8 Hz, 1H), 7.60 (t, J=7.6 Hz,1H), 7.23 (d, J=7.8 Hz, 1H), 7.11 (m, 1H), 6.58 (s, 1H), 6.56 (s, 1H),6.50 (s, 1H), 4.17 (t, J=6.2 Hz, 2H), 3.92 (t, J=6.1 Hz, 2H), 3.75 (t,J=7.4 Hz, 2H), 3.11 (t, J=7.5 Hz, 2H), 2.96 (s, 3H), 2.22 (s, 3H), 2.09(pentet, J=6.2 Hz, 2H), 1.49 (s, 18H).

b)3-[5-Methyl-3-(2-(N-methyl-N-(2-(2-pyridyl)ethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinedihydrochloride

The title compound was prepared in 89% yield fromN,N′-(bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-(2-(N-methyl-N-(2-(2-pyridyl)ethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidine,as prepared in the preceding step, in a manner analogous to step i ofExample 20. ¹H-NMR (300 MHz, DMSO-d₆) δ11.14 (br s, 2H), 8.58 (d, J=4.5Hz, 1H), 8.10 (d, J=7.8 Hz, 1H), 8.06 (d, J=7.8 Hz, 1H), 7.98 (t, J=7.7Hz, 2H), 7.57 (t, J=7.6 Hz, 1H), 7.71 (br s, 4H), 7.56 (br s, 1H), 7.47(m, 1H), 6.74 (s, 1H), 6.51 (s, 1H), 6.46 (s, 1H), 3.97 (t, J=6.2 Hz,2H), 3.90 (t, J=6.2 Hz, 2H), 3.74 (t, J=7.3 Hz, 2H), 3.17 (t, J=7.1 Hz,2H), 2.98 (s, 3H), 2.21 (s, 3H), 2.01 (pentet, J=6.2 Hz, 2H). Massspectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₂₅H₃₁N₅O₇S₂: 578.2 (M+H), 600.2 (M+Na). Found: 578.2, 600.0.

EXAMPLE 463-[5-Methyl-3-(2-(N-propyl-N-(2-(2-pyridyl)ethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinedihydrochloride

a)N,N′-(Bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-(2-(N-propyl-N-(2-(2-pyridyl)ethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidine

The title compound was prepared in 53% yield from2-[2-(N-propylamino)ethyl]pyridine in a manner analogous to step h ofExample 20. ¹H-NMR (300 MHz, CDCl₃) δ9.08 (s, 1H), 8.43 (d, J=4.9 Hz,1H), 8.22 (d, J=7.9 Hz, 1H), 8.07 (d, J=7.9 Hz, 1H), 7.75 (m, 3H), 7.61(t, J=7.7 Hz, 1H), 7.32 (m, 2H), 7.20 (m, 2H), 6.56 (s, 2H), 6.51 (s,1H), 4.17 (t, J=6.2 Hz, 2H), 3.92 (t, J=6.1 Hz, 2H), 3.82 (t, J=7.4 Hz,2H), 3.39 (t, J=7.5 Hz, 2H), 3.15 (t, J=6.6 Hz, 2H), 2.15 (s, 3H), 2.09(t, J=6.1 Hz, 2H), 1.61 (m, 2H), 1.49 (s, 18H), 0.84 (pentet, J=7.4 Hz,3H).

b)3-[5-Methyl-3-(2-(N-propyl-N-(2-(2-pyridyl)ethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinedihydrochloride

The title compound was prepared in 89% yield fromN,N′-(bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-(2-(N-propyl-N-(2-(2-pyridyl)ethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidine,as prepared in the preceding step, in a manner analogous to step i ofExample 20. ¹H-NMR (300 MHz, DMSO-d₆) δ11.08 (br s, 2H), 8.43 (d, J=4.0Hz, 1H), 8.11 (d, J=7.9 Hz, 1H), 8.09 (d, J=7.7 Hz, 1H), 7.95 (t, J=7.7Hz, 1H), 7.84 (t, J=7.7 Hz, 1H), 7.68 (br s, 5H), 7.27 (m, 2H), 6.73 (s,1H), 6.53 (s, 1H), 6.49 (s, 1H), 3.97 (t, J=6.2 Hz, 2H), 3.89 (t, J=6.3Hz, 2H), 3.71 (t, J=7.8 Hz, 2H), 3.34 (t, J=7.5 Hz, 2H), 3.01 (t, J=7.6Hz, 2H), 2.20 (s, 3H), 2.00 (pentet, J=6.2 Hz, 2H), 1.52 (m, 2H), 0.77(t, J=7.4 Hz, 3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamicacid matrix) calcd. for C₂₇H₃₅N₅O₇S₂: 606.2 (M+H), 628.2 (M+Na). Found:606.2, 628.3.

EXAMPLE 473-[5-Methyl-3-(2(N-ethyl-N-(4-pyridylmethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinedihydrochloride

a)N,N′-(Bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-(2-(N-ethyl-N-(4-pyridylmethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidine

The title compound was prepared in 48% yield from4-(N-ethyl)aminomethylpyridine in a manner analogous to step h ofExample 20. ¹H-NMR (300 MHz, CDCl₃) δ9.08 (s, 1H), 8.56 (d, J=4.7 Hz,2H), 8.37 (d, J=7.8 Hz, 1H), 8.16 (d, J=7.8 Hz, I1H), 7.77 (t, J=7.7 Hz,1H), 7.68 (d, J=7.8 Hz, 2H), 7.28 (m, 2H), 6.58 (s, 2H), 6.53 (s, 1H),4.70 (s, 2H), 4.17 (t, J=6.2 Hz, 2H), 3.93 (t, J=6.1 Hz, 2H), 3.32 (t,J=7.4 Hz, 2H), 2.23 (s, 3H), 2.09 (pentet, J=6.1 Hz, 2H), 1.49 (s, 18H),0.94 (t, J=7.2 Hz, 3H).

b){3-[5-Methyl-3-(2-(N-ethyl-N-(4-pyridylmethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidinedihydrochloride

The title compound was prepared in 84% yield fromN,N′-(Bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-(2-(N-ethyl-N-(4-pyridylmethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidine,as prepared in the preceding step, in a manner analogous to step i ofExample 20. ¹H-NMR (300 MHz, DMSO-d₆) δ8.54 (d, J=4.5 Hz, 2H), 8.23 (d,J=7.9 Hz, 1H), 8.17 (d, J=7.8 Hz, 1H), 8.01 (t, J=7.7 Hz, 1H), 7.89 (t,J=7.7 Hz, 1H), 7.42 (br s, 4H), 7.34 (d, J=5.8 Hz, 2H), 6.74 (s, 1H),6.54 (s, 1H), 6.50 (s, 1H), 4.67 (s, 2H), 3.97 (t, J=6.3 Hz, 2H), 3.87(t, J=6.3 Hz, 2H), 3.36 (t, J=7.1 Hz, 2H), 2.21 (s, 3H), 2.00 (pentet,J=6.1 Hz, 2H), 0.92 (t, J=7.1 Hz, 3H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₂₅H₃₁N₅O₇S₂: 578.2(M+H), 600.2 (M+Na), 616.1 (M+K). Found: 578.1, 599.9, 616.0.

EXAMPLE 483-[5-Methyl-3-(2-(N-methyl-N-(4-methoxyphenyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride

a)N,N′(Bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-(2-(N-methyl-N-(4-methoxyphenyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]phenoxy]propoxy}guanidine

The title compound was prepared in 80% yield from N-methyl-p-anisidinein a manner analogous to step h of Example 20. ¹H-NMR (300 MHz, CDCl₃)δ9.08 (s, 1H), 8.15 (d, J=7.6 Hz, 1H), 7,78 (d, J=7.6 Hz, 1H), 7.71 (brs, 1H), 7.57 (t, J=7.7 Hz, 2H), 7.11 (d, J=8.9 Hz, 2H), 6.77 (d, J=8.9Hz, 2H), 6.61 (s, 1H), 6.58 (s, 2H), 4.18 (t, J=6.1 Hz, 2H), 3.94 (t,J=6.2 Hz, 2H), 3.77 (s, 3H), 3.44 (s, 3H), 2.23 (s, 3H), 2.09 (pentet,J=6.1 Hz, 2H), 1.49 (s, 18H).

b)3-[5-Methyl-3-(2-(N-methyl-N-(4-methoxyphenyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride

The title compound was prepared in 92% yield fromN,N′-(Bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-(2-(N-methyl-N-(4-methoxyphenyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidine,as prepared in the preceding step, in a manner analogous to step i ofExample 20. ¹H-NMR (300 MHz, DMSO-d₆) δ11.04 (s, 1H), 8.16 (d, J=6.7 Hz,1H), 7.88 (m, 3H), 7.66 (br s, 4H), 7.16 (d, J=8.9 Hz, 2H), 6.88 (d,J=8.9 Hz, 2H), 6.673 (s, 1H), 6.48 (s, 2H), 3.97 (t, J=6.2 Hz, 2H), 3.90(t, J=6.3 Hz, 2H), 3.72 (s, 3H), 3.35 (s, 3H), 2.19 (s, 3H), 2.01(pentet, J=6.3 Hz, 2H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₂₅H₃₀N₄O₈S₂: 579.2(M+H), 601.1 (M+Na), 617.1 (M+K). Found: 579.1, 601.3, 617.2.

EXAMPLE 493-[5-Methyl-3-(2-(4-ethylpiperazin-1-ylsulonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinedihydrochloride

a)N,N′(Bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-(2-(4-ethylpiperazin-1-ylsulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidine

The title compound was prepared in 23% yield from N-ethylpiperazine in amanner analogous to step h of Example 20. ¹H-NMR (300 MHz, CDCl₃) δ9.08(s, 1H), 8.20 (t, J=8.2 Hz, 2H), 7.80 (t, J=7.8 Hz, 1H), 7.69 (m, 2H),6.57 (s, 2H), 6.51 (s, 1H), 4.18 (t, J=6.2 Hz, 2H), 3.94 (t, J=6.2 Hz,2H), 3.40 (t, J=4.8 Hz, 4H), 2.51 (t, J=4.8 Hz, 4H), 2.43 (q, J=7.2 Hz,2H), 2.23 (s, 3H), 2.10 (pentet, J=6.2 Hz, 2H), 1.49 (s, 18H), 1.05 (t,J 7.2 Hz, 3H).

b)3-[5-Methyl-3-(2-(4-ethylpiperazin-1-ylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinedihydrochloride

The title compound was prepared in 80% yield fromN,N′-(Bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-(2-(4-ethylpiperazin-1-ylsulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidine,as prepared in the preceding step, in a manner analogous to step i ofExample 20. ¹H-NMR (300 MHz, DMSO-d₆) δ11.06 (br s, 1H), 10.89 (br s,1H), 8.29 (d, J=7.9 Hz, 1H), 8.19 (d, J=7.9 Hz, 1H), 8.07 (t, J=7.8 Hz,1H), 7.94 (t, J=7.7 Hz, 1H), 7.66 (br s, 4H), 6.76 (s, 1H), 6.51 (s,1H), 6.48 (s, 1H), 3.99 (t, J=6.2 Hz, 2H), 3.90 (t, J=6.3 Hz, 2H), 3.52(br s, 2H), 3.33 (br s, 4H), 3.26 (br s, 2H), 3.13 (br s, 2H), 2.22 (s,3H), 2.02 (pentet, J=6.2 Hz, 2H), 1.21 (t, J=7.2 Hz, 3H). Mass spectrum(MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₂₃H₃₃N₅O₇S₂: 556.2 (M+H), 578.2 (M+Na), 594.1 (M+K). Found: 555.9,577.9, 593.7.

EXAMPLE 503-[5-Methyl-3-(2-(N-methyl-N-(4-methoxycarbonylphenyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride

a)N,N-(Bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-(2-(N-methyl-N-(4-methoxycarbonylphenyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidine

The title compound was prepared in 80% yield from methyl4-methylaminobenzoate in a manner analogous to step h of Example 20.¹H-NMR (300 MHz, CDCl₃) δ9.11 (s, 1H), 8.14 (d, J=9.0Hz, 1H), 7.94 (d,J=8.8 Hz, 2H), 7.86 (d, J=9.1 Hz, 1H), 7.60 (m, 2H), 7.34 (d, J=8.8 Hz,2H), 6.58 (s, 1H), 6.54 (s, 1H), 6.51 (s, 1H), 4.18 (t, J=6.1 Hz, 2H),3.93 (t, J=6.1 Hz, 2H), 3.89 (s, 3H), 3.51 (s, 3H), 2.22 (s, 3H), 2.10(pentet, J=6.0 Hz, 2H), 1.49 (s, 18H).

b){3-[5-Methyl-3-(2-(N-methyl-N-(4-methoxycarbonylphenyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidinehydrochloride

The title compound was prepared in 92% yield fromN,N′-(Bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-(2-(N-methyl-N-(4-methoxycarbonylphenyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidine,as prepared in the preceding step, in a manner analogous to step i ofExample 20. ¹H-NMR (300 MHz, DMSO-d₆) δ11.07 (br s, 1H), 8.17 (d, J=7.5Hz, 1H), 7.88-7.99 (m, 5H), 7.67 (br s, 4H), 7.43 (d, J=7.7 Hz, 2H),6.74 (s, 1H), 6.45 (s, 2H), 3.98 (t, J=6.2 Hz, 2H), 3.90 (t, J=6.3 Hz,2H), 3.83 (s, 3H), 3.46 (s, 3H), 2.19 (s, 3H), 2.02 (pentet, J=6.2 Hz,2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix)calcd. for C₂₆H₃₀N₄O₉S₂: 607.2 (M+H), 629.1 (M+Na). Found: 606.9, 628.8.

EXAMPLE 513-[5-Methyl-3-(2-(N-(2-cyanoethyl)-N-(3-pyridylmethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinedihydrochloride

a)N,N′-(Bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-(2-(N-(2-cyanoethyl)-N-(3-pyridylmethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidine

The title compound was prepared in 66% yield from3-(3-pyridylmethylamino)propionitrile in a manner analogous to step h ofExample 20. ¹H-NMR (300 MHz, CDCl₃) δ9.08 (s, 1H), 8.56 (br s, 1H), 8.50(br s, 1H), 8.35 (d, J=7.7 Hz, 1H), 8.18 (d, J=7.8 Hz, 1H), 7.81 (t,J=7.7 Hz, 1H), 7.72 (m, 3H), 7.29 (t, J=7.7 Hz, 1H), 6.60 (s, 1H), 6.57(s, 1H), 6.52 (s, 1H), 4.70 (s, 2H), 4.17 (t, J=6.2 Hz, 2H), 3.94 (t,J=6.2 Hz, 2H), 3.65 (t, J=7.0 Hz, 2H), 2.50 (t, J=7.0 Hz, 2H), 2.24 (s,3H), 2.12 (pentet, J=6.3 Hz, 2H), 1.49 (s, 18H).

b)3-[5-Methyl-3-(2-(N-(2-cyanoethyl)-N-(3-pyridylmethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinedihydrochloride

The title compound was prepared in 91% yield fromN,N′-(bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-(2-(N-(2-cyanoethyl)-N-(3-pyridylmethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidine,as prepared in the preceding step, in a manner analogous to step i ofExample 20. ¹H-NMR (300 MHz, DMSO-d₆) δ11.09 (s, 1H), 8.70 (m, 2H), 8.27(d, J=7.9 Hz, 1H), 8.15 (t, J=7.8 Hz, 2H), 8.01 (t, J=7.7 Hz, 1H), 7.91(t, J=7.7 Hz, 1H), 7.75 (t, J=7.7 Hz, 1H), 7.68 (br s, 4H), 6.75 (s,1H), 6.54 (s, 1H), 6.51 (s, 1H), 4.81 (s, 2H), 3.99 (t, J=6.2 Hz, 2H),3.90 (t, J=6.3 Hz, 2H), 3.68 (t, J=6.7 Hz, 2H), 2.73 (t, J=6.6 Hz, 2H),2.22 (s, 3H), 2.01 (pentet, J=6.3 Hz, 2H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₂₆H₃₀N₆O₇S₂: 603.2(M+H), 625.1 (M+Na); Found: 603.0, 624.9.

EXAMPLE 523-[5-Methyl-3-(2-(N,N-bis-(2-cyanoethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride

a)N,N′-(Bis-tert-butyloxycarbonyl)-N″-{3-[5-methyl-3-(2-(N,N-bis-(2-cyanoethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidine

The title compound was prepared in 46% yield from3,3′-iminodipropionitrile in a manner analogous to step h of Example 20.¹H-NMR (300 MHz, CDCl₃) δ9.08 (s, 1H), 8.39 (d, J=7.9 Hz, 1H), 8.19 (d,J=7.8 Hz, 1H), 7.88 (t, J=7.7 Hz, 1H), 7.76 (t, J=7.7 Hz, 1H), 7.70 (s,1H), 6.60 (s, 1H), 6.55 (s, 1H), 6.49 (s, 1H), 4.17 (t, J=6.2 Hz, 2H),3.94 (t, J=6.2 Hz, 2H), 3.78 (t, J=6.8 Hz, 4H), 2.73 (t, J=6.8 Hz, 4H),2.24 (s, 3H), 2.10 (pentet, J=6.2 Hz, 2H), 1.49 (s, 18H).

b)3-[5-Methyl-3-(2-(N,N-bis-(2-cyanoethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride

The title compound was prepared in 85% yield fromN,N′-(bis-tert-butyloxycarbonyl)-N″-{3-[5-methyl-3-(2-(N,N-bis-(2-cyanoethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidine,as prepared in the preceding step, in a manner analogous to step i ofExample 20. ¹H-NMR (300 MHz, DMSO-d₆) δ11.05 (br s, 1H), 8.25 (d, J=7.9Hz, 1H), 8.14 (d, J=7.8 Hz, 1H), 8.01 (t, J=7.7 Hz, 1H), 7.90 (t, J=7.7Hz, 1H), 7.66 (br s, 4H), 6.74 (s, 1H), 6.54 (s, 1H), 6.51 (s, 1H), 3.99(t, J=6.2 Hz, 2H), 3.91 (t, J=6.3 Hz, 2H), 3.71 (t, J=6.8 Hz, 4H), 2.84(t, J=6.8 Hz, 4H), 2.22 (s, 3H), 2.02 (pentet, J=6.2 Hz, 2H). Massspectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₂₃H₂₈N₆O₇S_(2::) 565.2 (M+H), 587.1 (M+Na); Found: 565.2, 587.0.

EXAMPLE 533-[5-Methyl-3-(2-(N-(2-ethoxycarbonylethyl)-N-benzylaminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride

a)N,N′-(Bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-(2-(N-(2-ethoxycarbonylethyl)-N-benzylaminosulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidine

The title compound was prepared in 74% yield fromN-benzyl-3-aminopropionic acid ethyl ester in a manner analogous to steph of Example 20. ¹H-NMR (300 MHz, CDCl₃) δ9.02 (s, 1H), 8.76 (s, 1H),8.16 (t, J=8.1 Hz, 2H), 7.98 (t, J=7.7 Hz, 1H), 7.88 (t, J=7.8 Hz, 1H),7.34 (m, 5H), 6.74 (s, 1H), 6.54 (s, 1H), 6.47 (s, 1H), 4.63 (s, 2H),3.91 (m, 6H), 3.53 (t, J=7.2 Hz, 2H), 2.37 (t, J=7.3 Hz, 4H), 2.21 (s,3H), 1.96 (pentet, J=6.2 Hz, 2H), 1.39 (s, 18H), 1.09 (t, J=7.1 Hz, 3H).

b)3-[5-Methyl-3-(2-(N-(2-ethoxycarbonylethyl)-N-benzylaminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride

The title compound was prepared in 92% yield fromN,N′-(bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-(2-(N-(2-ethoxycarbonylethyl)-N-benzylaminosulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidine,as prepared in the preceding step, in a manner analogous to step i ofExample 20. ¹H-NMR (300 MHz, DMSO-d₆) δ11.10 (br s, 1H, 8.18 (t, J=8.8Hz, 2H), 7.99 (t, J=7.7 Hz, 1H), 7.89 (t, J=7.8 Hz, 1H), 7.69 (br s,4H), 7.34 (m, 5H), 6.75 (s, 1H), 6.54 (s, 1H), 6.52 (s, 1H), 4.63 (s,2H), 3.98 (t, J=6.2 Hz, 2H), 3.91 (q, J=7.0 Hz, 4H), 3.53 (t, J=7.3 Hz,2H), 2.38 (t, J=7.3 Hz, 4H), 2.21 (s, 3H), 2.01 (pentet, J=6.2 Hz, 2H),1.09 (t, J=7.1 Hz, 3H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₂₉H₃₆N₄O₉S₂: 649.2(M+H), 671.2 (M+Na); Found: 649.0, 671.0.

EXAMPLE 543-[5-Methyl-3-(2-(4-(piperidin-1-yl)piperidin-1-ylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinedihydrochloride

a)N,N′-(Bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-(2-(4-(piperidin-1-yl)piperidin-1-ylsulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidine

The title compound was prepared in 37% yield from 4-piperidinopiperidinein a manner analogous to step h of Example 20. ¹H-NMR (300 MHz, CDCl₃)δ9.08 (s, 1H), 8.31 (d, J=7.9 Hz, 1H), 8.15 (d, J=7.9 Hz, 1H), 7.82 (t,J=7.7 Hz, 1H), 7.70 (m, 2H), 6.60 (s, 1H), 6.52 (s, 1H), 6.47 (s, 1H),4.17 (t, J=6.2 Hz, 2H), 4.07 (m, 2H), 3.94 (t, J=6.2 Hz, 2H), 2.88 (m,3H), 2.27 (m, 2H), 2.24 (s, 3H), 2.10 (pentet, J=6.2 Hz, 2H), 1.51-1.96(m, 10H), 1.49 (s, 18H), 1.25 (m, 2H).

b)3-[5-Methyl-3-(2-(4-(piperidiny1-yl)piperidin-1-ylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinedihydrochloride

The title compound was prepared in 88% yield fromN,N′-(Bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-(2-(4-(piperidin-1-yl)piperidin-1-ylsulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidine,as prepared in the preceding step, in a manner analogous to step i ofExample 20. ¹H-NMR (300 MHz, DMSO-d₆) δ11.10 (br s, 1H), 10.29 (br s,1H), 8.24 (d, J=7.9 Hz, 1H), 8.17 (d, J=7.9 Hz, 1H), 8.03 (t, J=7.7 Hz,1H), 7.91 (t, J=7.7 Hz, 1H), 7.68 (br s, 4H), 6.75 (s, 1H), 6.52 (s,1H), 6.48 (s, 1H), 3.98 (t, J=6.2 Hz, 4H), 3.90 (t, J=6.3 Hz, 2H), 3.35(m, 5H), 2.88 (m, 4H), 2.22 (s, 3H), 2.16 (m, 2H), 2.02 (pentet, J=6.3Hz, 2H), 1.67-1.79 (m, 6H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₂₇H₃₉N₅O₇S₂: 610.2(M+H), 632.2 (M+Na), 648.2 (M+K); Found: 610.1, 632.0, 648.1.

EXAMPLE 55{3-[5-Methyl-3-(2-(N-methyl-N-(2-(4-pyridyl)ethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidinedihydrochloride

a)N,N′-(Bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-(2-(N-methyl-N-(2-(4-pyridyl)ethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidine

The title compound was prepared in 15% yield from4-[(2-methylamino)ethyl]pyridine in a manner analogous to step h of Eg.20. ¹H-NMR (300 MHz, CDCl₃) δ9.08 (s, 1H), 8.55 (d, J=5.1 Hz, 2H), 8.24(d, J=7.7 Hz, 1H), 8.12 (d, J=7.8 Hz, 1H), 7.69 (m, 3H), 7.30 (m, 2H),6.58 (s, 1H), 6.54 (s, 1H), 6.48 (s, 1H), 4.18 (t, J=6.2 Hz, 2H), 3.92(t, J=6.2 Hz, 2H), 3.65 (t, J=7.3 Hz, 2H), 3.05 (t, J=7.4 Hz, 2H), 2.90(s, 3H), 2.23 (s, 3H), 2.08 (pentet, J=6.2 Hz, 2H), 1.49 (s, 18H).

b){3-[5-Methyl-3-(2-(N-methyl-N-(2-(4-pyridyl)ethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidinedihydrochloride

The title compound was prepared in 83% yield fromN,N′-(bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-(2-(N-methyl-N-(2-(4-pyridyl)ethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidine,as prepared in the preceding step, in a manner analogous to step i ofExample 20. ¹H-NMR (300 MHz, CDCl₃/CD₃OD) δ8.72 (br s, 2H), 8.15 (t,J=7.8 Hz, 2H), 7.65-7.95 (m, 3H), 7.74 (t, 7.4 Hz, 1H), 6.64 (s, 1H),6.60 (s, 1H), 6.45 (s, 1H), 4.03 (br s, 2H), 3.94 (br s, 2H), 3.83 (brs, 2H), 3.39 (m, 2H), 2.98 (s, 3H), 2.27 (s, 3H), 2.07 (m, 2H). Massspectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₂₅H₃₁N₅O₇S₂: 578.2 (M+H), 600.2 (M+Na); Found: 578.0, 599.9.

EXAMPLE 563-[5-Methyl-3-(2-(N-(ethoxycarbonylmethyl)-N-(2-pyridylmethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinedihydrochloride

a)N,N′-(Bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-(2-(N-(ethoxycarbonylmethyl)-N-(2-pyridylmethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidine

The title compound was prepared in 38% yield fromN-(pyridylmethyl)glycine ethyl ester in a manner analogous to step h ofExample 20. ¹H-NMR (300 MHz, CDCl₃), δ9.05 (s, 1H), 8.47 (d, J=4.0 Hz,1H), 8.37 (d, J=7.8 Hz, 1H), 8.14 (d, J=7.9 Hz, 1H), 7.75 (t, J=7.7 Hz,1H), 7.63 (m, 3H), 7.40 (t, J=7.9 Hz, 1H), 6.57 (s, 2H), 6.53 (s, 1H),4.73 (s, 3H), 4.31 (s, 3H), 4.16 (t, J=6.2 Hz, 2H), 4.02 (q, J=7.1 Hz,2H), 3.92 (t, J=6.1 Hz, 2H), 2.21 (s, 3H), 2.07 (pentet, J=6.2 Hz, 2H),1.49 (s, 18H), 1.15 (t, J=7.1 Hz, 3H).

b)3-[5-Methyl-3-(2-(N-(ethoxycarbonylmethyl)-N-(2-pyridylmethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinedihydrochloride

The title compound was prepared in 90% yield fromN,N′-(Bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-(2-(N-(ethoxycarbonylmethyl)-N-(2-pyridylmethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidine,as prepared in the preceding step, in a manner analogous to step i ofExample 20. ¹H-NMR (300 MHz, DMSO-d₆) δ8.54 (d, J=4.4 Hz, 1H), 8.39 (d,J=7.8 Hz, 1H), 8.14 (d, J=7.8 Hz, 1H), 7.97 (t, J=7.7 Hz, 1H), 7.87 (t,J=7.8 Hz, 2H), 7.67 (br s, 4H), 7.43 (t, J=7.7 Hz, 2H), 6.75 (s, 1H),6.53 (s, 1H), 6.50 (s, 1H), 4.76 (s, 3H), 4.36 (s, 3H), 3.97 (q, J=7.1Hz, 2H), 3.90 (t, J=6.5 Hz, 4H), 2.22 (s, 3H), 2.02 (pentet, J=6.4 Hz,2H), 1.06 (t, J=7.1 Hz, 3H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₂₇H₃₃N₅O₉S₂: 636.2(M+H), 658.2 (M+Na); Found: 636.0, 658.0.

EXAMPLE 573-[5-Methyl-3-(2-(N,N-bis(ethoxycarbonylmethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride

a)N,N′-(Bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-(2-(N,N-bis(ethoxycarbonylmethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidine

The title compound was prepared in 76% yield from diethyl iminodiacetatein a manner analogous to step h of Eg. 20. ¹H-NMR (300 MHz, CDCl₃) δ9.07(s, 1H), 8.35 (d, J=7.9 Hz, 1H), 8.15 (d, J=7.8 Hz, 1H), 7.79 (t, J=7.7Hz, 1H), 7.69 (d, J=7.9 Hz, 1H), 7.66 (t, J 7.7 Hz, 1H), 6.57 (s, 2H),6.52 (s, 1H), 4.35 (s, 4H), 4.18 (t, J 6.2 Hz, 2H), 4.12 (q, J=7.1 Hz,4H), 3.94 (t, J=6.2 Hz, 2H), 2.23 (s, 3H), 2.10 (pentet, J 6.2 Hz, 2H),1.49 (s, 18H), 1.21 (t, J=7.1 Hz, 6H).

b)3-[5-Methyl-3-(2-(N,N-bis(ethoxycarbonylmethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride

The title compound was prepared in 74% yield fromN,N′-(bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-(2-(N,N-bis(ethoxycarbonylmethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]preparedin the preceding step, in a manner analogous to step i of Example 20.¹H-NMR (300 MHz, DMSO-d₆) δ8.41 (d, J=7.9 Hz, 1H), 8.13 (d, J=7.8 Hz,1H), 7.98 (t, J=7.7 Hz, 1H), 7.88 (d, J=7.8 Hz, 1H), 7.65 (br s, 4H),6.75 (s, 1H), 6.52 (s, 1H), 6.49 (s, 1H), 4.30 (s, 4H), 4.99 (q, J=7.1Hz, 6H), 3.91 (t, J=6.3 Hz, 2H), 2.22 (s, 3H), 2.02 (pentet, J=6.2 Hz,2H), 1.10 (t, J=7.1 Hz, 6H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₂₅H₃₄N₄O₁₁S₂: 631.2(M+H), 653.2 (M+Na); Found: 630.9, 653.1.

EXAMPLE 583-[5-Methyl-3-(2-(4-(ethoxycarbonylmethyl)piperaziny1-ylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinedihydrochloride

a)N,N′-(Bis-tert-butyloxycarbonyl)-{3-[5-methyl-3-(2-(4-ethoxycarbonylmethyl)piperazin-1-ylsulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidine

The title compound was prepared in 74% yield from1-(ethoxycarbonylmethyl)piperazine in a manner analogous to step h ofExample 20. ¹H-NMR (300 MHz, CDCl₃) δ9.08 (s, 1H), 8.23 (d, J=7.9 Hz,1H), 8.19 (d, J=7.9 Hz, 1H), 7.80 (t, J=7.7 Hz, 1H), 7.71 (s, 1H), 7.68(t, J=7.8 Hz, 1H), 6.59 (s, 1H), 6.56 (s, 1H), 6.51 (s, 1H), 4.17 (m,4H), 3.94 (t, J=6.2 Hz, 2H), 3.47 (t, J=4.6 Hz, 4H), 3.25 (s, 2H), 2.72(m, 4H), 2.23 (s, 3H), 2.10 (pentet, J=6.2 Hz, 2H), 1.49 (s, 18H), 1.26(t, J=7.2 Hz, 3H).

b)3-[5-Methyl-3-(2-(4-(ethoxycarbonylmethyl)piperazin-1-ylsulfonyl)henylsulfonyloxy)phenoxy]propoxyguanidinedihydrochloride

The title compound was prepared in 82% yield fromN,N′-(bis-tert-butyloxycarbonyl)-3-[5-methyl-3-(2-(4-(ethoxycarbonylmethyl)piperazin-1-ylsulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidine,as prepared in the preceding step, in a manner analogous to step i ofExample 20. ¹H-NMR (300 MHz, DMSO-d₆) δ11.15 (s, 1H), 8.27 (d, J=7.8 Hz,1H), 8.18 (d, J=7.8 Hz, 1H), 8.07 (t, J=7.7 Hz, 1H), 7.94 (t, J=7.8 Hz,1H), 7.71 (br s, 4H), 6.75 (s, 1), 6.51 (s, 1H), 6.47 (s, 1H), 4.18 (q,J=7.1 Hz , 2H), 3.98 (t, J=6.2 Hz, 2H), 3.90 (t, J=6.3 Hz, 2H), 3.56 (brs, 6H), 3.20 (br s, 4H), 2.22 (s, 3H), 2.02 (pentet, J=6.2 Hz, 2H), 1.22(t, J=7.2 Hz, 3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamicacid matrix) calcd. for C₂₅H₃₅N₅O₉S₂: 614.2 (M+H), 636.2 (M+Na), 652.2(M+K). Found 614.1, 636.0, 652.1.

EXAMPLE 59 3-[5-Methyl-3-(2-M-bis(carboxymethyl)aminosulfonyl)phenylsulfonyl)phenoxy]propoxyguanidine

The title compound was prepared in 87% yield from3-[5-methyl-3-(2-(N,N-bis(ethoxycarbonylmethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride, as prepared in step b of Example 57, in a manneranalogous to Example 27. ¹H-NMR (300 MHz, DMSO-d₆) δ8.29 (d, J=7.0 Hz,1H), 8.10 (d, J=7.6 Hz, 1H), 7.97 (t, J=7.6 Hz, 1H), 7.84 (t, J=7.6 Hz,1H), 7.63 (br s, 4H), 6.72 (s, 1H), 6.58 (s, 1H), 6.49 (s, 1H), 4.13 (s,4H), 3.97 (t, J=6.3 Hz, 2H), 3.90 (t, J=6.3 Hz, 2H), 2.23 (s, 3H), 2.03(pentet, J=6.2 Hz, 2H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₂₁H₂₆N₄O₁₁S₂: 575.1(M+H), 597.1 (M+Na), 613.1 (M+K). Found: 575.1, 597.0, 613.1.

EXAMPLE 603-[5-Methyl-3-(2-(N-methyl-N-(4-carboxyphenyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine

The title compound was prepared in 84% yield from3-[5-methyl-3-(2-(N-methyl-N-(4-methoxycarbonylphenyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride, as prepared in step b of Example 50, in a manneranalogous to Example 27. ¹H-NMR (300 MHz, DMSO-d₆) δ8.17 (d, J=7.4 Hz,1H), 7.97 (t, J=7.6 Hz, 1H), 7.90 (m, 4H), 7.61 (br s, 4H), 7.40 (d,J=7.7 Hz, 2H), 6.74 (s, 1H), 6.45 (s, 2H), 3.98 (t, J=6.2 Hz, 2H), 3.90(t, J=6.3 Hz, 2H), 3.46 (s, 3H), 2.19 (s, 3H), 2.01 (pentet, J=6.2 Hz,2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix)calcd. for C₂₅H₂₈N₄O₉S₂: 593.1 (M+H), 615.1 (M+Na), 631.1 (M+K). Found:593.1, 615.0, 630.9.

EXAMPLE 613-[5-Methyl-3-(2-(N-(2-carboxyethyl)-N-benzylaminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine

The title compound was prepared in 97% yield from3-[5-methyl-3-(2-(N-(2-ethoxycarbonylethyl)-N-benzylaminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride as prepared in step b of Example 53, in a manner analogousto Example 27. ¹H-NMR (300 MHz, DMSO-d₆) δ8.19 (t, J=7.9 Hz, 2H), 7.99(t, J=7.7 Hz, 1H), 7.88 (t, J=7.8 Hz, 1H), 7.56 (br s, 4H), 7.34 (m,5H), 6.74 (s, 1H), 6.54 (s, 1H), 6.51 (s, 1H), 4.63 (s, 2H), 3.97 (t,J=6.2 Hz, 2H), 3.89 (t, J=6.1 Hz, 2H), 3.51 (t, J=7.4 Hz, 2H), 2.28 (t,J=7.5 Hz, 4H), 2.22 (s, 3H), 1.99 (pentet, J=6.1 Hz, 2H). Mass spectrum(MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₂₇H₃₂N₄O₉S₂: 621.2 (M+H), 643.2 (M+Na). Found: 621.0, 642.9.

EXAMPLE 62{3-[5-Methyl-3-(2-(4-(carboxymethyl)piperazinN-1-ylsulfonyl)phenylsulfonyloxy)phenoxy]propoxylguanidine

The title compound was prepared in 85% yield from{3-[5-methyl-3-(2-(4-(ethoxycarbonylmethyl)piperazin-1-ylsulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidinedihydrochloride, as prepared in step b of Example 58, in a manneranalogous to Example 27. ¹H-NMR (300 MHz, DMSO-d₆) δ11.12 (s, 1H), 8.27(d, J=7.9 Hz, 1H), 8.18 (d, J=7.9 Hz, 1H), 8.08 (t, J=7.7 Hz, 1H), 7.94(t, J=7.7 Hz, 1H), 7.69 (br s, 4H), 6.76 (s, 1H), 6.51 (s, 1H), 6.47 (s,1H), 3.99 (t, J=6.2 Hz, 2H), 3.90 (t, J=6.3 Hz, 2H), 3.43 (br s, 6H),3.25 (br s, 4H), 2.22 (s, 3H), 2.02 (pentet, J=6.2 Hz, 2H). Massspectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₂₃H₃₁N₅O₉S₂: 586.2 (M+H), 608.1 (M+Na). Found: 586.2, 608.0.

EXAMPLE 633-[5-methyl-3-(2-(4-(2-pyridyl)piperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride

a)N,N′-Bis-(tert-butoxycarbonyl)-3-[5-methyl-3-(2-(4-(2-pyridyl)piperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine

The title compound was prepared in 67% yield from1-(2-pyridyl)piperazine, in a manner analogous to step h of Eg. 20. ¹HNMR (300 MHz, CDCl₃) δ9.08 (s, 1H), 8.28 (dd, 1H, J=7.9, 1.3 Hz), 8.16(m, 2H), 7.81 (td, 1H, J=7.7, 1.4 Hz), 7.68 (m, 2H), 7.48 (m, 1H), 6.61(m, 4H), 6.51 (t, 1H, J=2.1 Hz), 4.18 (m, 2H), 3.94 (t, 2H, J=6.2 Hz),3.63 (m, 4H), 3.48 (m, 4H), 2.23 (s, 3H), 2.10 (m, 2H), 1.49 (s, 18H).

b)3-[5-methyl-3-(2-(4-(2-pyridyl)piperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride

The title compound was prepared in quantitative yield fromN,N′-bis-(tert-butoxycarbonyl)-3-[5-methyl-3-(2-(4-(2-pyridyl)piperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine,as prepared in the previous step, in a manner analogous to step i ofExample 20 (without chromatographic purification). ¹H NMR (300 MHz,CDCl₃/CD₃OD) δ8.33 (d, 1H, J=6.9 Hz), 8.20 (dd, 1H, J=7.8, 1.1 Hz), 8.11(dd, 1H, J=6.0, 1.5 Hz), 7.90 (m, 2H), 7.78 (m, 1H), 7.06 (d, 1H, J=8.9Hz), 6.93 (t, 1H, J=6.6 Hz), 6.63 (m, 2H), 6.50 (t, 1H, J=2.1 Hz), 4.06(t, 2H, J=6.0 Hz), 4.01 (t, 2H, J=5.9 Hz), 3.89 (m, 4H), 3.60 (m, 4H),2.28 (s, 3H), 2.10 (pentet, 2H, J=5.9 Hz). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₂₆H₃₂N₆O₇S₂: 605.2(M+H), 627.2 (M+Na). Found: 605.0, 627.1.

EXAMPLE 643-[5-methyl-3-(2-(4-phenylpiperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride

a) N,NBis-(tert-butoxycarbonyl)-3-[5-methyl-3-(2-(4-phenylpiperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine

The title compound was prepared in 40% yield from 1-phenylpiperazine, ina manner analogous to step h of Example 20. ¹H NMR (300 MHz, CDCl₃)δ9.08 (s, 1H), 8.28 (dd, 1H, J=7.9, 1.3 Hz), 8.19 (dd, 1H, J=7.9, 1.4Hz), 7.81 (td, 1H, J=7.7, 1.4 Hz), 7.69 (m, 2H), 7.27 (m, 4H), 6.89 (m,3H), 6.58 (br s, 2H), 6.52 (t, 1H, J=2.1 Hz), 4.18 (t, 2H, J=6.2Hz),3.94 (t, 2H, J=6.2 Hz), 3.43 (m, 4H), 3.24 (m, 4H), 2.24 (s, 3H), 2.10(m, 2H), 1.49 (s, 18H).

b)3-[5-methyl-3-(2-(4-phenylpiperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride

The title compound was prepared in quantitative yield fromN,N′-bis-(tert-butoxycarbonyl)-3-[5-methyl-3-(2-(4-phenylpiperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine,as prepared in the previous step, in a manner analogous to step i ofExample 20 (without chromatographic purification). ¹H NMR (300 MHz,CDCl₃/CD₃OD) δ8.34 (d, 1H, J=7.3 Hz), 8.21 (d, 1H, J=7.6 Hz), 7.94 (m,1H), 7.83 (t, 1H, J=7.4 Hz), 7.74 (d, 2H, J=7.7 Hz), 7.50 (m, 3H), 6.64(s, 1H), 6.57 (s, 1H), 6.53 (s, 1H), 4.03 (m, 18H), 3.67 (m, 4H), 2.26(s, 3H), 2.12 (m, 2H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₂₇H₃₃N₅O₇S₂: 604.2(M+H), 626.2 (M+Na). Found: 604.2, 626.3.

EXAMPLE 653-[5-methyl-3-(2-(4-benzylpiperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride

a)N,N′-Bis-(tert-butoxycarbonyl)-3-[5-methyl-3-(2-(4-benzylpiperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine

The title compound was prepared in 75% yield from 1-benzylpiperazine, ina manner analogous to step h of Example 20. ¹H NMR (300 MHz, CDCl₃)δ9.08 (s, 1H), 8.21 (m, 1H), 8.17 (dd, 1H, J=6.6, 1.4 Hz), 7.78 (td, 1H,J=7.7, 1.5 Hz), 7.70 (s, 1H), 7.66 (td, 1H, J=7.7, 1.4 Hz), 7.28 (m,5H), 6.57 (m, 2H), 6.51 (t, 1H, J=2.1 Hz), 4.18 (t, 2H, J=6.2 Hz), 3.94(t, 2H, J=6.2 Hz), 3.52 br s, 2H), 3.40 (br s, 4H), 2.53 (br s, 4H),2.23 (s, 3H), 2.08 (m, 2H), 1.49 (s, 18H).

b)3-[5-methyl-3-(2-(4-benzylpiperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride

The title compound was prepared in quantitative yield fromN,N′-bis-(tert-butoxycarbony)-3-[5-methyl-3-(2-(4-benzylpiperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine,as prepared in the previous step, in a manner analogous to step i ofExample 20 (without chromatographic purification). ¹H NMR (300 MHz,CDCl₃/CD₃OD) δ8.26 (d, 1H, J=7.6 Hz), 8.16 (d, 1H, J=7.7 Hz,), 7.91 (m,1H), 7.78 (m, 1H), 7.60 (m, 2H), 7.44 (m, 4H), 6.62 (s, 1H), 6.54 (s,1H), 6.48 (s, 1H), 4.32 (s, 2H), 4.00 (m, 2H), 3.66 (m, 2H), 3.49 (m,2H), 3.13 (m, 2H), 2.24 (s, 3H), 2.10 (m, 2H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₂₈H₃₅N₅O₇S₂: 618.2(M+H). Found: 618.2.

EXAMPLE 663-[5-methyl-3-(2-(4(2-methoxyphenyl)piperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride

a)N,N′-Bis-(tert-butoxycarbony)-3-[5-methyl-3-(2-(4-(2-methoxyphenyl)piperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine

The title compound was prepared in 79% yield from1-(2-methoxyphenyl)piperazine, in a manner analogous to step h ofExample 20. ¹H NMR (300 MHz, CDCl₃) δ9.09 (s, 1H), 8.24 (dd, 1H, J=7.9,1.3 Hz), 8.21 (dd, 1H, J=8.0, 1.4 Hz), 7.81 (td, 1H, J=7.7, 1.4 Hz),7.69 (m, 2H), 7.02 (m, 1H), 6.90 (m, 3H), 6.59 (m, 2H), 6.53 (t, 1H,J=2.1 Hz), 4.18 (t, 2H, J=6.2 Hz), 3.95 (t, 2H, J=6.2 Hz), 3.83 (s, 3H),3.55 (m, 4H), 3.13 (br t, 4H, J=4.8 Hz), 2.24 (s, 3H), 2.10 (pentet, 2H,J=6.2 Hz), 1.49 (s, 18H).

b)3-[5-methyl-3-(2-(4-(2-methoxyphenyl)piperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride

The title compound was prepared in 33% yield fromN,N′-bis-(tert-butoxycarbony)-3-[5-methyl-3-(2-(4-(2-methoxyphenyl)piperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine,as prepared in the previous step, in a manner analogous to step i ofExample 20 (without HCl-methanol acidification). ¹H NMR (300 MHz, CDCl₃)δ8.21 (m, 2H), 7.81 (t, 1H, J=7.5 Hz), 7.69 (t, 1H, J=7.5 Hz), 7.00 (m,1H), 6.89 (m, 3H), 6.58 (s, 2H), 6.53 (s, 1H), 3.95 (m, 4H), 3.82 (s,3H), 3.53 (m, 4H), 3.11 (m, 4H), 2.22 (s, 3H), 2.03 (m, 2H). Massspectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₂₈H₃₅N₅O₈S₂: 634.2 (M+H), 656.2 (M+Na). Found: 634.2, 656.3.

EXAMPLE 673-[5-methyl-3-(2-(N-(2-cyanoethyl)-N-(2-furanylmethyl)aminosulfonyl)phenylsulfonyloxy)phenylsulfonyloxy)phenoxy]propoxyguanidine

a)N,N′-Bis-(tert-butoxycarbony)-3-5-methyl-3-(2-(N-(2-cyanoethyl)-N-(2-furanylmethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]proxyguanidine

The title compound was prepared in 49% yield from3-(furfurylamino)propionitrile, in a manner analogous to step h ofExample 20. ¹H NMR (300 MHz, CDCl₃) δ9.08 (s, 1H), 8.29 (dd, 1H, J=7.9,1.4 Hz), 8.16 (dd, 1H, J=7.8, 1.5 Hz), 7.79 (m, 1H), 7.70 (m, 2H), 7.33(t, 1H, J=1.3 Hz), 6.60 (m, 1H), 6.57 (m, 1H), 6.52 (t, 1H, J=2.1 Hz),6.32 (m, 2H), 4.65 (s, 2H), 4.18 (t, 2H, J=6.2 Hz), 3.94 (t, 2H, J=6.2Hz), 3.65 (m, 2H), 2.55 (m, 2H), 2.24 (s, 3H), 2.10 (pentet, 2H, J=6.2Hz), 1.49 (s, 18H).

b)3-[5-methyl-3-(2-(N-(2-cyanoethyl)-N-(2-furanylmethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine

The title compound was prepared in 42% yield fromN,N′-bis-(tert-butoxycarbony)-3-[5-methyl-3-(2-(N-(2-cyanoethyl)-N-(2-furanylmethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine,as prepared in the previous step, in a manner analogous to step i ofExample 20 (without HCl-methanol acidification). ¹H NMR (300 MHz, CDCl₃)δ8.23 (dd, 1H, J=7.9, 1.3 Hz), 8.14 (dd, 1H, J=7.9, 1.4 Hz), 7.76 (td,1H, J=7.7, 1.4 Hz), 7.67 (td, 1H, J=7.7, 1.3 Hz), 7.29 (t, 1H, J=1.3Hz), 6.56 (m, 2H), 6.51 (m, 1H), 6.28 (m, 2H), 4.61 (s, 2H), 3.91 (m,4H), 3.62 (t, 2H J=7.1 Hz), 2.53 (t, 2H, J=7.1 Hz), 2.20 (s, 3H), 2.00(pentet, 2H, J=6.1 Hz). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₂₅H₂₉N₅O₈S₂: 592.2(M+H), 614.1 (M+Na). Found: 592.2, 614.4.

EXAMPLE 683-[5-Methyl-3-(2-(4-methylpiperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride

a) N-3-[(3-Hydroxy-5-methyl)phenoxy]propoxyphthalimide

A mixture of N-3-[(3-benzyloxy-5-methyl)phenoxy]propoxyphthalimide (9.19g, 22.0 mmol), as prepared in step c of Example 20, and 10% palladium oncarbon (516 mg) in tetrahydrofuran (100 mL) and ethanol (100 mL) wasstirred at room temperature under hydrogen (balloon) for 3 hours. Thecatalyst was removed by filtration over Celite, the filtrate wasconcentrated and the remaining solid was purified by trituration withcold methanol giving the title compound as a pale yellow solid (5.72 g,79%). ¹H NMR (300 MHz, CDCl₃/CD₃OD) δ7.83 (m, 2H), 7.77 (m, 2H), 6.26(m, 3H), 4.40 (t, 2H, J=6.3 Hz), 4.17 (t, 2H, J=6.2 Hz), 2.23 (m, 5H).

b)3-[5-Methyl-3-(2-chlorosulfonyl)phenylsulfonyloxy)phenoxy]propoxyphthalimide

A mixture of 1,2-benzenedisulfonic anhydride (1.74 g, 7.91 mmol), asprepared in step g of Example 20, N-3-[(3-hydroxy-5-methyl)phenoxy]propoxyphthalimide (2.59 g, 7.92 mmol), as prepared in the previousstep, and N,N-diisopropylethylamine (1.40 mL, 8.05 mmol) in anhydrousdichloromethane (100 mL) was stirred at room temperature under nitrogen(balloon) for 18 hours. Oxalyl chloride (1.40 ML, 16.0 mmol) andN,N-dimethylformamide (0.02 mL) were added and the reaction stirredanother 4 hours at room temperature. The solution was concentrated andthe residue was purified by flash chromatography (dichloromethane)giving the title compound as a white solid (3.31 g, 74%). ¹H NMR (300MHz, CDCl₃) δ8.48 (dd, 1H, J=7.6, 1.7 Hz), 8.25 (dd, 1H, J=7.5, 1.8 Hz),7.90 (m, 4H), 7.77 (m, 2H), 6.66 (m, 1H), 6.62 (br s, 1H), 6.53 (t, 1H,J=2.2 Hz), 4.37 (t, 2H, J=6.1 Hz), 4.13 (t, 2H, J=6.1 Hz), 2.27 (s, 3H),2.19 (pentet, 2H, J=6.1 Hz). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₂₇H₃₃N₅O₇S₂: 588.0(M+Na). Found: 588.2.

c)3-[5-Methyl-3-(2-(4-methylpiperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyphthalimide

A mixture of3-[5-methyl-3-(2-chlorosulfonyl)phenylsulfonyloxy)phenoxy]propoxyphthalimide(181 mg, 0.32 mmol), as prepared in the previous step,1-methylpiperazine (34 mg, 0.34 mmol), and N,N-diisopropylethylamine(0.06 mL, 0.35 mmol) in anhydrous CH₂Cl₂ (10 mL) was stirred at roomtemperature under nitrogen (balloon) for 4 hours. The solution wasconcentrated and the residue was purified by flash chromatography (2.5%to 5% methanol in dichloromethane) giving the title compound as a whitesolid (161 mg, 80%). ¹H NMR (300 MHz, CDCl₃) δ8.24 (dd, 1H, J=7.9, 1.3Hz), 8.19 (dd, 1H, J=7.9, 1.4 Hz), 7.84 (m, 2H), 7.77 (m, 3H), 7.68 (td,1H, J=7.7, 1.3 Hz), 6.62 (br s, 1H), 6.59 (br s, 1H), 6.51 (t, 1H, J=2.2Hz), 4.36 (t, 2H, J=6.2 Hz), 4.10 (t, 2H, J=6.1 Hz), 3.40 (m, 4H), 2.47(br t, 4H, J=4.9 Hz), 2.28 (s, 3H), 2.25 (s, 3H), 2.18 (pentet, 2H,J=6.1Hz).

d)3-[5-Methyl-3-(2-(4-methylpiperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyamine

A mixture3-[5-methyl-3-(2-(4-methylpiperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyphthalimide(156 mg, 0.25 mmol), as prepared in the previous step, and 40% aqueousmethylamine (1.50 mL, 21.5 mmol) in tetrahydrofuran (5 mL) and ethanol(5 mL) was stirred at room temperature for 4 hours. The solution wasconcentrated and the residue was purified by flash chromatography (10%methanol in dichloromethane) giving a slurry that was twice dissolved indiethyl ether, filtered, and concentrated giving the title compound as aclear oil (113 mg, 91%). ¹H NMR (300 MHz, CDCl₃/CD₃OD) δ8.22 (dd, 1H,J=7.9, 1.3 Hz), 8.18 (dd, 1H, J=7.9, 1.4 Hz), 7.83 (td, 1H, J=7.7, 1.4Hz), 7.70 (td, 1H, J=7.7, 1.3 Hz), 6.60 (br s, 1H), 6.56 (br s, 1H),6.53 (t, 1H, J=2.1 Hz), 3.93 (t, 2H, J=6.3 Hz), 3.80 (t, 2H, J=6.2 Hz),3.41 (m, 5H), 2.50 (br t, 4H, J=4.9 Hz), 2.30 (s, 3H), 2.24 (s, 3H),2.00 (pentet, 2H, J=6.2 Hz).

e)3-[5-Methyl-3-(2-(4-methylpiperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride

A mixture of3-[5-methyl-3-(2-(4-methylpiperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyamine(113 mg, 0.23 mmol), as prepared in the previous step, and1H-pyrazole-1-carboxamidine hydrochloride (62 mg, 0.42 mmol) inanhydrous N,N-dimethylformamide (10 mL) was stirred at room temperatureunder nitrogen (balloon) for 18 hours. The solution was concentratedunder high vacuum with heating and the residue was purified by flashchromatography (10% to 20% methanol in dichloromethane), then dissolvedin dichloromethane, filtered and concentrated to give the title compound(105 mg, 80%) as a white solid. ¹H NMR (300 MHz, CDCl₃) δ8.20 (m, 2H),7.83 (td, 1H, J=7.7, 1.3 Hz), 7.70 (td, 1H, J=7.7, 1.2 Hz), 6.59 (m,2H), 6.52 (m, 1H), 6.28 (m, 3H), 4.04 (t, 2H, J=5.8 Hz), 3.96 (t, 2H,J=5.8 Hz), 3.43 (m, 4H), 2.33 (s, 3H), 2.23 (s, 3H), 2.00 (m, 2H). Massspectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₂₂H₃₁N₅O₇S₂: 542.2 (M+H), 564.2 (M+Na). Found: 542.3, 564.3.

EXAMPLE 69 {3-[5-Methyl-3-(2-(N-ethyl-N-(1-benzyl-3-pyrrolidinyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidine dihydrochloride

a)N-{3-[5-Methyl-3-[(2-(N-ethyl-N-(1-benzyl-3-pyrrolidinyl)aminosulfonyl)phenylsulfonyloxy]phenoxy]propoxy}phthalimide

The title compound was prepared in 98% yield from1-benzyl-3-(ethylamino)pyrrolidine in a manner analogous to step c ofExample 68. ¹H-NMR (300 MHz, CDCl₃) δ8.36 (br s, 1H), 8.13 (d, J=7.7 Hz,1H), 7.75-7.86 (m, 5H), 7.68 (t, J=7.8 Hz, 1H), 7.34-7.57 (m, 5H), 6.62(s, 1H), 6.56 (s, 1H), 6.51 (s, 1H), 4.36 (t, J=6.1 Hz, 2H), 4.10 (m,4H), 3.50-4.16 (m, 4H), 2.31 (m 1H), 2.24 (s, 3H), 2.17 (pentet, J=6.1Hz, 2H), 1.62 (m, 4H), 1.26 (t, J=7.1 Hz, 3H).

b)N-{3-5-Methyl-3-[(2-(N-ethyl-N-(1-benzyl-3-pyrrolidinyl)aminosulfonyl)phenylsulfonyloxy]phenoxy]propoxy}amine

The title compound was prepared in 83% yield fromN-{3-[5-methyl-3-[(2-(N-ethyl-N-(1-benzyl-3-pyrrolidinyl)aminosulfonyl)phenylsulfonyloxy]phenoxy]propoxy}amine,as prepared in the preceding step, in a manner analogous to step d ofExample 68. ¹H-NMR (300 MHz, CDCl₃) δ8.26 (d, J=7.9 Hz, 1H), 8.12 (d,J=7.9 Hz, 1H), 7.73 (t, J=7.7 Hz, 1H), 7.61 (t, J=7.7 Hz, 1H), 7.26 (m,5H), 6.57 (s, 3H), 5.37 (br s, 2H), 4.56 (br s, 1H), 3.91 (t, J=6.3 Hz,2H), 3.78 (t, J=6.2 Hz, 2H), 3.57 (m, 4H), 2.80 (m, 1H), 2.69 (m, 1H),2.50 (m, 1H), 2.22 (s, 3H), 1.96 (pentet, J=6.2 Hz, 2H), 1.85 (m, 1H),1.62 (br s, 2H), 1.22 (t, J=7.1 Hz, 3H).

c)N-{3-[5-Methyl-3-[(2-(N-ethyl-N-(1-benzyl-3-pyrrolidinyl)aminosulfonyl)phenylsulfonyloxy]phenoxy]propoxy}guanidinedihydrochloride

The title compound was prepared in 83% yield fromN-{3-[5-methyl-3-[(2-(N-ethyl-N-(1-benzyl-3-pyrrolidinyl)aminosulfonyl)phenylsulfonyloxy]phenoxy]propoxy}phthalimide,as prepared in the preceding step, in a manner analogous to step f ofExample 1. ¹H-NMR (300 MHz, DMSO-d₆) δ11.15 (br s, 2H), 8.18 (d, J=7.8Hz, 1H), 8.14 (d, J=7.8 Hz, 1H), 8.00 (t, J=7.6 Hz, 1H), 7.88 (t, J=7.7Hz, 1H), 7.68 (br s, 4H), 7.38 (m, 5H), 6.74 (s, 1H), 6.52 (s, 1H), 6.48(s, 1H), 4.66 (br s, 1H), 4.04 (m, 1H), 3.97 (t, J=6.3 Hz, 2H), 3.89 (t,J=6.3 Hz, 2H), 3.50 (m, 2H), 2.75-3.20 (m, 5H), 2.21 (s, 3H), 2.13 (m,2H), 2.01 (pentet, J=6.2 Hz, 2H), 1.10 (t, J=6.9 Hz, 3H). Mass spectrum(MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₃₀H₃₉N₅O₇S₂: 646.2 (M+H). Found: 646.0.

EXAMPLE 703-[5-Methyl-3-(2-(N-benzyl-N-(2-(N,N-dimethylamino)ethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinedihydrochloride

a)N-{3-5-Methyl-3-[(2-(N-benzyl-N-(2-(N,N-dimethylamino)ethyl)aminosulfonyl)phenylsulfonyloxy]phenoxy]propoxy}phthalimide

The title compound was prepared in 100% yield fromN-benzyl-N,N-dimethylethylenediamine in a manner analogous to step c ofExample 68. ¹H-NMR (300 MHz, CDCl₃) δ8.26 (d, J=7.8 Hz, 1H), 8.18 (d,J=7.8 Hz, 1H), 7.83 (m, 2H), 7.76 (m, 3H), 7.67 (t, J=7.6 Hz, 1H), 7.32(m, 5H), 6.62 (s, 2H), 6.55 (s, 1H), 4.63 (s, 2H), 4.35 (t, J=6.3 Hz,2H), 4.10 (t, J=6.1 Hz, 2H), 3.65 (t, J=6.8 Hz, 2H), 2.55 (t, J=6.8 Hz,2H), 2.33 (s, 6H), 2.25 (s, 3H), 2.17 (pentet, J=6.2 Hz, 2H).

b)N-{3-[5-Methyl-3-[(2-(N-benzyl-N-(2-(N,N-dimethylamino)ethyl)aminosulfonyl)phenylsulfonyloxy]phenoxy]propoxy}amine

The title compound was prepared in 95% yield fromN-{3-[5-methyl-3-[(2-(N-benzyl-N-(2-(N,N-dimethylamino)ethyl)aminosulfonyl)phenylsulfonyloxy]phenoxy]propoxy}phthalimide,as prepared in the preceding step, in a manner analogous to step d ofExample 68. ¹H-NMR (300 MHz, CDCl₃) δ8.36 (d, J=7.8 Hz, 1H), 8.16 (d,J=7.8 Hz, 1H), 7.73 (t, J=7.7 Hz, 1H), 7.63 (t, J=7.7 Hz, 1H), 7.31 (m,5H), 6.62 (s, 1H), 6.59 (s, 2H), 5.37 (br s, 2H), 4.68 (s, 2H), 3.92 (t,J=6.3 Hz, 2H, 3.78 (t, J=6.2 Hz, 2H), 3.38 (t, J=7.0 Hz, 2H), 2.26 (t,J=7.1 Hz, 2H), 2.23 (s, 3H), 2.06 (s, 6H), 1.99 (pentet, J=6.2 Hz, 2H).

c)3-[5-Methyl-3-(2-(N-benzyl-N-(2-(N,N-dimethylamino)ethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinedihydrochloride

The title compound was prepared in 76% yield fromN-{3-[5-methyl-3-[(2-(N-benzyl-N-(2-(N,N-dimethylamino)ethyl)aminosulfonyl)phenylsulfonyloxy]phenoxy]propoxy}amine,as prepared in the preceding step, in a manner analogous to step f ofExample 1. ¹H-NMR (300 MHz, DMSO-d₆) δ11.98 (br s, 2H), 8.18 (d, J=7.7Hz, 1H), 8.16 (d, J=7.7 Hz, 1H), 7.96 (t, J=7.7 Hz, 1H), 7.89 (t, J=7.7Hz, 1H), 7.69 (br s, 4H), 7.34 (m, 5H), 6.76 (s, 1H), 6.55 (s, 1H), 6.51(s, 1H), 4.64 (s, 2H), 3.98 (t, J=6.2 Hz, 2H), 3.89 (t, J=6.3 Hz, 2H),3.69 (t, J=7.1 Hz, 2H), 2.85 (br s, 2H), 2.51 (s, 6H), 2.22 (s, 3H),2.01 (pentet, J=6.3 Hz, 2H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₂₈H₃₇N₅O₇S₂: 620.2(M+H), 642.2 (M+Na). Found: 620.2, 642.1.

EXAMPLE 71{3-[5-Methyl-3-(2-(N-methyl-N-(-methyl-4-piperidinyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxy]guanidinedihydrochloride

a)N-{3-[5-Methyl-3-[(2-(N-methyl-N-(1-methyl-4-piperidinyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxy}phthalimide

The title compound was prepared in 96% yield from1-methyl-4-(methylamino)piperidine in a manner analogous to step c ofExample 68. ¹H-NMR (300 MHz, CDCl₃) δ8.33 (d, J=7.8 Hz, 1H), 8.14 (d,J=7.9 Hz, 1H), 7.83 (m, 3H), 7.78 (m, 2H), 7.69 (t, J=7.6 Hz, 1H), 6.63(s, 1H), 6.54 (s, 1H), 6.51 (s, 1H), 4.61 (m, 1H), 4.36 (t, J=6.1 Hz,2H), 4.10 (t, J=6.1 Hz, 2H), 4.39 (m, 2H), 2.92 (t, J=12.0 Hz, 2H), 2.79(s, 3H), 2.74 (s, 3H), 2.55 (m, 2H), 2.24 (s, 3H), 2.17 (pentet, J=6.1Hz, 2H), 1.99 (m, 2H).

b)N-{3-[5-Methyl-3-[(2-(N-methyl-N-(1-methyl-4-piperidinyl)aminosulfonyl)phenylsulfonyloxy]phenoxy]propoxy}amine

The title compound was prepared in 88% yield fromN-{3-[5-methyl-3-[(2-(N-methyl-N-(1-methyl-4-piperidinyl)aminosulfonyl)phenylsulfonyloxy]phenoxy]propoxy}amine,as prepared in the preceding step, in a manner analogous to step d ofExample 68. ¹H-NMR (300 MHz, CDCl₃) δ8.30 (d, J=7.9 Hz, 1H), 8.13 (d,J=7.9 Hz, 1H), 7.78 (t, J=7.6 Hz, 1H), 7.64 (t, J=7.6 Hz, 1H), 6.58 (s,1H), 6.56 (s, 1H), 6.54 (s, 1H), 5.36 (br s, 2H), 4.06 (m, 1H), 3.91 (t,J=6.3 Hz, 2H), 3.79 (t, J=6.2 Hz, 2H), 2.90 (m, 2H), 2.83 (s, 3H), 2.28(s, 3H), 2.23 (s, 3H), 2.11 (m, 2H), 1.99 (pentet, J=6.1 Hz, 2H), 1.84(m, 2H), 1.68 (m, 2H).

c)N-{3-[5-Methyl-3-[(2-(N-methyl-N-(1-methyl-4-piperidinyl)aminosulfonyl)phenylsulfonyloxy]phenoxy]propoxy}guanidinedihydrochloride

The title compound was prepared in 76% yield fromN-{3-[5-methyl-3-[(2-(N-methyl-N-(1-methyl-4-piperidinyl)aminosulfonyl)phenylsulfonyloxy]phenoxy}phthalimide,as prepared in the preceding step, in a manner analogous to step f ofExample 1. ¹H-NMR (300 MHz, DMSO-d₆), δ8.25 (d, J=7.9 Hz, 1H), 8.15 (d,J=7.9 Hz, 1H), 8.02 (t, J=7.6 Hz, 1H), 7.89 (t, J=7.7 Hz, 1H), 7.37 (brs, 4H), 6.75 (s, 1H), 6.53 (s, 1H), 6.47 (s, 1H), 4.07 (m, 1H), 3.97 (t,J=6.3 Hz, 2H), 3.87 (t, J=6.3 Hz, 2H), 3.22 (m, 2H), 3.17 (s, 3H), 2.79(s, 3H), 2.72 (t, J=12.0 Hz, 2H), 2.22 (s, 3H), 1.99 (pentet, J=6.3 Hz,4H), 1.60 (m, 2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamicacid matrix) calcd. for C₂₄H₃₅N₅O₇S₂: 570.2 (M+H), 592.2 (M+Na). Found:570.1, 592.1.

EXAMPLE 72 3-[5-Methyl-3-(2-(N-methyl-N-(3-pyridylmethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine dihydrochloride

a)N-{3-[5-Methyl-3-[(2-(N-methyl-N-(3-pyridylmethyl)aminosulfonyl)phenylsulfonyloxy]phenoxy]propoxy}phthalimide

The title compound was prepared in 88% yield from3-(methylaminomethyl)pyridine in a manner analogous to step c of Example68. ¹H-NMR (300 MHz, CDCl₃) δ8.56 (m, 2H), 8.35 (d, J=7.9 Hz, 1H), 8.21(d, J=7.9 Hz, 1H), 7.69-7.86 (m, 7H), 7.32 (m, 1H), 6.64 (s, 1H), 6.62(s, 1H), 6.54 (s, 1H), 4.61 (s, 2H), 4.36 (t, J=6.1 Hz, 2H), 4.11 (t,J=6.1 Hz, 2H), 2.77 (s, 3H), 2.26 (s, 3H), 2.18 (pentet, J=6.1 Hz, 2H).

b)3-[5-Methyl-3-[(2-(N-methyl-N-(3-pyridylmethyl)aminosulfonyl)phenylsulfonyloxy]phenoxy]propoxyamine

The title compound was prepared in 90% yield fromN-{3-[5-methyl-3-[(2-(N-methyl-N-(3-pyridylmethyl)aminosulfonyl)phenylsulfonyloxy]phenoxy]propoxy}phthalimide,as prepared in the preceding step, in a manner analogous to step d ofExample 68. ¹H-NMR (300 MHz, CDCl₃) δ8.56 (m, 2H), 8.34 (d, J=7.9 Hz,1H), 8.20 (d, J=7.9 Hz, 1H), 7.81 (t, J=7.7 Hz, 2H), 7.70 (t, J=7.7 Hz,1H), 7.32 (m, 1H), 6.60 (s, 1H), 6.58 (s, 1H), 6.57 (s, 1H), 4.60 (s,2H), 3.93 (t, J=6.3 Hz, 2H), 3.78 (t, J=6.1 Hz, 2H), 2.77 (s, 3H), 2.24(s, 3H), 2.00 (pentet, J=6.2 Hz, 2H).

c) 3-[5-Methyl-3-[(2-(N-methyl-N-(3-pyridylmethyl)aminosulfonyl)phenylsulfonyloxy]phenoxy]propoxyguanidine dihydrochloride

The title compound was prepared in 76% yield from3-[5-methyl-3-[(2-(N-methyl-N-(3-pyridylmethyl)aminosulfonyl)phenylsulfonyloxy]phenoxy]propoxyamine,as prepared in the preceding step, in a manner analogous to step f ofExample 1. ¹H-NMR (300 MHz, DMSO-d₆) δ8.78 (t, J=5.2 Hz, 2H), 8.23 (m,3H), 8.06 (t, J=7.7 Hz, 1H), 7.94 (t, J=7.7 Hz, 1H), 7.88 (t, J=7.9 Hz,1H), 7.71 (br s, 4H), 6.75 (s, 1H), 6.55 (s, 1H), 6.51 (s, 1H), 4.72 (s,2H), 3.99 (t, J=6.3 Hz, 2H), 3.90 (t, J=6.4 Hz, 2H), 2.88 (s, 3H), 2.22(s, 3H), 2.01 (pentet, J=6.4 Hz, 2H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₂₄H₂₉N₅O₇S₂: 564.2(M+H), 586.1 (M+Na). Found: 564.1, 586.2.

EXAMPLE 73 3-[5-Methyl-3-(2-(N-ethyl-N-(2-(N,N-dimethylamino)ethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine dihydrochloride

a)3-[5-Methyl-3-(2-(N-ethyl-N-(2-(N,N-dimethylamino)ethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyphthalimide

The title compound was prepared in 100% yield fromN,N-dimethyl-N′-ethylethylenediamine in a manner analogous to step c ofExample 68. ¹H-NMR (300 MHz, CDCl₃) δ8.27 (d, J=7.9 Hz, 1H), 8.18 (d,J=7.9 Hz, 1H), 7.75-7.86 (m, 5H), 7.69 (t, J=7.7 Hz, 1H), 6.61 (s, 1H),6.58 (s, 1H), 6.52 (s, 1H), 4.36 (t, J=6.2 Hz, 2H), 4.10 (t, J=6.1 Hz,2H), 3.81 (br s, 2H), 3.45 (q, J=7.1 Hz, 2H), 3.00 (br s, 2H), 2.59 (s,6H), 2.24 (s, 3H), 2.17 (pentet, J=6.1 Hz, 2H), 1.21 (t, J=7.1 Hz, 3H).

b)3-[5-Methyl-3-(2-(N-ethyl-N-(2-(N,N-dimethylamino)ethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyamine

The title compound was prepared in 97% yield from3-[5-methyl-3-(2-(N-ethyl-N-(2-(N,N-dimethylamino)ethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyphthalimide, as prepared in the preceding step, in a manner analogous tostep d of Example 68. ¹H-NMR (300 MHz, CDCl₃) δ8.32 (d, J=7.9 Hz, 1H),8.15 (d, J=7.9 Hz, 1H), 7.76 (t, J=7.7 Hz, 1H), 7.63 (t, J=7.7 Hz, 1H),6.60 (s, 1H), 6.58 (s, 1H), 6.57 (s, 1H), 5.39 (br s, 2H), 3.92 (t,J=6.3 Hz, 2H), 3.78 (t, J=6.1 Hz, 2H), 3.49 (m, 4H), 2.46 (t, J=7.1 Hz,2H), 2.23 (s, 3H), 2.21 (s, 6H), 1.99 (pentet, J=6.2 Hz, 2H), 1.16(t,J=7.1 Hz, 3H).

c)3-[5-Methyl-3-(2-(N-ethyl-N-(2-(N,N-dimethylamino)ethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinedihydrochloride

The title compound was prepared in 52% yield from3-[5-methyl-3-(2-(N-ethyl-N-(2-(N,N-dimethylamino)ethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyamine,as prepared in the preceding step, in a manner analogous to step f ofExample 1. ¹H-NMR (300 MHz, DMSO-d₆) δ8.19 (d, J=7.8 Hz, 1H), 8.17 (d,J=7.8 Hz, 1H), 8.03 (t, J=7.7 Hz, 1H), 7.90 (t, J=7.7 Hz, 1H), 7.69 (brs, 4H), 6.75 (s, 1H), 6.53 (s, 1H), 6.50 (s, 1H), 3.98 (t, J=6.2 Hz,2H), 3.90 (t, J=6.3 Hz, 2H), 3.78 (t, J=7.0 Hz, 2H), 3.44 (q, J=7.1 Hz,2H), 3.30 (t, J=7.3 Hz, 2H), 2.79 (s, 6H), 2.22 (s, 3H), 2.02 (pentet,J=6.3 Hz, 2H), 1.09 (t, J=7.1 Hz, 3H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₂₃H₃₅N₅O₇S₂: 558.2(M+H), 580.2 (M+Na). Found: 558.3, 580.3.

EXAMPLE 743-[5-Methyl-3-(2-(2-(4-morpholinyl)ethylaminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinedihydrochloride

a)3-[5-Methyl-3-(2-(2-(4-morpholinyl)ethylaminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyphthalimide

The title compound was prepared in 96% yield from4-(2-aminoethyl)morpholine in a manner analogous to step c of Example68. ¹H-NMR (300 MHz, CDCl₃) δ8.37 (d, J=7.8 Hz, 1H), 8.08 (d, J=7.8 Hz,1H), 7.75-7.86 (m, 5H), 7.70 (t, J=7.7 Hz, 1H), 6.68 (s, 1H), 6.63 (s,1H), 6.58 (s, 1H), 6.53 (s, 1H), 4.36 (t, J=6.1 Hz, 2H), 4.11 (t, J=6.1Hz, 2H), 3.89 (m, 6H), 3.48 (m, 6H), 2.24 (s, 3H), 2.18 (pentet, J=6.1Hz, 2H).

b)3-[5-Methyl-3-(2-(2-(4-morpholinyl)ethylaminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyamine

The title compound was prepared in 96% yield from3-[5-methyl-3-(2-(2-(4-morpholinyl)ethylaminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyphthalimide,as prepared in the preceding step, in a manner analogous to step d ofExample 68. ¹H-NMR (300 MHz, CDCl₃) δ8.36 (d, J=7.8 Hz, 1H), 8.06 (d,J=7.8 Hz, 1H), 7.81 (t, J=7.7 Hz, 1H), 7.66 (t, J=7.7 Hz, 1H), 6.68 (s,1H), 6.60 (s, 1H), 6.58 (s, 1H), 6.56 (s, 1H), 3.90 (t, J=6.1 Hz, 2H),3.79 (t, J=6.1 Hz, 2H), 3.67 (br s, 4H), 3.14 (br s, 2H), 2.36 (m, 6H),2.23 (s, 3H), 1.99 (pentet, J=6.2 Hz, 2H).

c)3-[5-Methyl-3-(2-(2-(4-morpholinyl)ethylaminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinedihydrochloride

The title compound was prepared in 60% yield from3-[5-methyl-3-(2-(2-(4-morpholinyl)ethylaminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyamine,as prepared in the preceding step, in a manner analogous to step f ofExample 1. ¹H-NMR (300 MHz, DMSO-d₆) δ8.28 (d, J=7.8 Hz, 1H), 8.11 (d,J=7.8 Hz, 1H), 8.05 (t, J=7.7 Hz, 1H), 7.95 (br s, 1H), 7.90 (t, J=7.7Hz, 1H), 7.72 (br s, 4H), 6.76 (s, 1H), 6.55 (s, 1H), 6.50 (s, 1H), 3.98(t, J=6.3 Hz, 2H), 3.91 (t, J=6.3 Hz, 2H), 3.79 (m, 4H), 3.25 (br s,4H), 3.17 (m, 4H), 2.23 (s, 3H), 2.02 (pentet, J=6.3 Hz, 2H). Massspectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₂₃H₃₃N₅O₈S₂: 572.2 (M+H), 594.2 (M+Na). Found: 572.3, 594.4.

EXAMPLE 753-[5-Methyl-3-(2-(N-methyl-N-(2-(N,N-dimethylamino)ethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride

a)3-[5-Methyl-3-(2-(N-methyl-N-(2-(N,N-dimethylamino)ethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyphthalimide

The title compound was prepared in 98% yield fromN,N,N′-trimethylethylenediamine, in a manner analogous to step c ofExample 68 and was used without characterization.

b)3-[5-Methyl-3-(2-(N-methyl-N-(2-(N,N-dimethylamino)ethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyamine

The title compound was prepared in 66% yield from3-[5-methyl-3-(2-(N-methyl-N-(2-(N,N-dimethylamino)ethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyphthalimide,as prepared in the previous step, in a manner analogous to step d ofExample 68, and was used without characterization.

c)3-[5-Methyl-3-(2-(N-methyl-N-(2-(N,N-dimethylamino)ethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride

A mixture of3-[5-methyl-3-(2-(N-methyl-N-(2-(N,N-dimethylamino)ethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyamine(94 mg, 0.19 mmol) and 1H-pyrazole-1-carboxamidine hydrochloride (57 mg,0.39 mmol), in N,N-dimethylformamide (8 mL) was stirred at roomtemperature for 18 hours then concentrated in vacuo. The residue wasdissolved in acetonitrile, filtered, and the filtrate concentrated to anoil. This was dissolved in dilute HCl (pH 3), washed with diethyl ether,basified with aqueous NaHCO₃, and extracted with CH₂Cl₂. The CH₂Cl₂layer was washed with pH 7 buffer and brine, dried over Na₂SO₄ andfiltered. The filtrate was acidified with HCl-methanol and concentratedgiving the title compound as a white solid (100 mg, 92%). ¹H NMR (300MHz, CDCl₃) δ8.20 (m, 2H), 7.93 (td, 1H, J=7.7, 1.4 Hz), 7.78 (td, 1H,J=7.7, 1.2 Hz), 6.62 (m, 2H), 6.51 (t, 1H, J=2.2 Hz), 4.05 (t, 2H, J=6.1Hz), 3.99 (t, 2H, J=6.0 Hz), 3.87 (t, 2H, J=6.9 Hz), 3.44 (t, 2H, J=6.9Hz), 3.04 (s, 3H), 2.96 (s, 6H), 2.27 (s, 3H), 2.10 (m, 2H). Massspectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₂₂H₃₃N₅O₇S₂: 544.2 (M+H). Found: 544.0.

EXAMPLE 763-[5-Methyl-3-(2-(4-(pyrrolidin-1-yl)piperidin-1-ylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine

a)3-[5-Methyl-3-(2-(4-(pyrrolidin-1-yl)piperidin-1-ylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyphthalimide

The title compound was prepared in 99% yield from4-(1-pyrrolidinyl)piperidine, in a manner analogous to step c of Example68, and was used without characterization.

b)3-[5-Methyl-3-(2-(4-(pyrrolidin-1-yl)piperidin-1-ylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyamine

The title compound was prepared in 66% yield from3-[5-methyl-3-(2-(4-(pyrrolidin-1-yl)piperidin-1-ylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyphthalimide,as prepared in the previous step, in a manner analogous to step d ofExample 68, and was used without characterization.

c)3-[5-Methyl-3-(2-(4-(pyrrolidin-1-yl)piperidin-1-ylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine

The title compound was prepared in 76% yield from3-[5-methyl-3-(2-(4-(pyrrolidin-1-yl)piperidin-1-ylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyamine,as prepared in the previous step, in a manner analogous to step c of Eg.75 (without acidification with HCl—MeOH). ¹H NMR (300 MHz, CDCl₃) δ8.25(dd, 1H, J=7.9, 1.3 Hz), 8.17 (dd, 1H, J=7.9, 1.4 Hz), 7.78 (td, 1H,J=7.7, 1.4 Hz,), 7.66 (td, 1H, J=7.7, 1.4 Hz), 6.59 (m, 2H), 6.54 (t,1H, J=2.2 Hz), 3.92 (m, 6H), 2.93 (m, 2H), 2.59 (m, 4H), 2.24 (s, 3H),1.99 (m, 5H), 1.79 (m, 4H), 1.65 (m, 2H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₂₆H₃₇N₅O₇S₂: 596.2(M+H). Found: 595.9.

EXAMPLE 773-[5-Methyl-3-(2-(4-ethoxycarbonyl-1-piperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride

a)3-[5-Methyl-3-(2-(4-ethoxycarbonyl-1-piperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyphthalimide

The title compound was prepared in 97% yield from ethylN-piperazinecarboxylate, in a manner analogous to step c of Example 68.¹H NMR (300 MHz, CDCl₃) δ8.29 (dd, 1H, J=7.9, 1.4 Hz), 8.18 (dd, 1H,J=7.8, 1.4 Hz), 7.81 (m, 5H), 7.70 (td, 1H, J=7.7, 1.4 Hz), 6.63 (m,1H), 6.58 (m, 1H), 6.49 (t, 1H, J=2.2 Hz), 4.12 (m, 4H), 3.55 (m, 4H),3.36 (br s, 4H), 2.25 (s, 3H), 2.18 (pentet, 2H, J=6.1 Hz), 1.24 (t, 3H,J=7.1 Hz).

b)3-[5-Methyl-3-(2-(4-ethoxycarbonyl-1-piperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyamine

The title compound was prepared in quantitative yield from3-[5-methyl-3-(2-(4-ethoxycarbonyl-1-piperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyphthalimide,as prepared in the previous step, in a manner analogous to step d ofExample 68, and was used without characterization.

c)3-[5-Methyl-3-(2-(4-ethoxycarbonyl-1-piperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride

The title compound was prepared in 78% yield from3-[5-methyl-3-(2-(4-ethoxycarbonyl-1-piperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyamine,as prepared in the previous step, in a manner analogous to step c ofExample 75. ¹H NMR (300 MHz, CDCl₃) δ8.24 (d, 1H, J=7.6 Hz), 8.18 (d,1H, J=7.6 Hz), 7.84 (t, 1H, J=7.5 Hz), 7.73 (t, 1H, J=7.5 Hz), 6.58 (brs, 2H), 6.50 (s, 1H), 4.11 (q, 2H, J=7.1 Hz), 4.07 (m, 2H), 3.96 (m,2H), 3.55 (m, 4H), 3.34 (m, 4H), 2.23 (s, 3H), 2.08 (m, 2H), 1.23 (t,3H, J=7.1 Hz). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acidmatrix) calcd. for C₂₄H₃₃N₅O₉S₂: 600.2 (M+H), 622.6 (M+Na). Found:600.3, 622.2.

EXAMPLE 783-[5-Methyl-3-(2-(N-methyl-N-(3-(N,N-dimethylamino)propyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine

a)3-[5-Methyl-3-(2-(N-methyl-N-(3-(N,N-dimethylamino)propyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyphthalimide

The title compound was prepared in 97% yield fromN,N,N′-trimethyl-1,3-propanediamine, in a manner analogous to step c ofExample 68. ¹H NMR (300 MHz, CDCl₃) δ8.23 (dd, 1H, J=7.9, 1.3 Hz), 8.16(dd, 1H, J=7.9, 1.4 Hz), 7.81 (m, 5H), 7.66 (td, 1H, J=7.7, 1.4 Hz),6.61 (m, 2H), 6.53 (t, 1H, J=2.1 Hz), 4.36 (t, 2H, J=6.2 Hz), 4.10 (t,2H, J=6.1 Hz), 3.39 (t, 2H, J=7.3 Hz), 2.95 (s, 3H), 2.32 (m, 2H), 2.24(s, 3H), 2.21 (s, 6H), 2.16 (m, 2H), 1.80 (m, 2H).

b)3-[5-Methyl-3-(2-(N-methyl-N-(3-(N,N-dimethylamino)propyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyamine

The title compound was prepared in quantitative yield from3-[5-methyl-3-(2-(N-methyl-N-(3-(N,N-dimethylamino)propyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyphthalimide,as prepared in the previous step, in a manner analogous to step d ofExample 68, and was used without characterization.

c)3-[5-Methyl-3-(2-(N-methyl-N-(3-(N,N-dimethylamino)propyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine

The title compound was prepared in 78% yield from3-[5-methyl-3-(2-(N-methyl-N-(3-(N,N-dimethylamino)propyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyamine,as prepared in the previous step, in a manner analogous to step c ofExample 75 (without acidification with HCl-methanol). ¹H NMR (300 MHz,CDCl₃/CD₃OD) δ8.18 (dd, 1H, J=5.2, 1.4 Hz), 8.15 (dd, 1H, J=5.2, 1.4Hz), 7.83 (td, 1H, J=7.7, 1.4 Hz), 7.70 (td, 1H, J=7.7, 1.4 Hz), 6.60(m, 1H), 6.57 (m, 1H), 6.52 (t, 1H, J=2.2 Hz), 3.95 (t, 2H, J=6.3 Hz),3.92 (t, 2H, J=6.1 Hz), 3.37 (m, 2H), 2.95 (s, 3H), 2.38 (m, 2H), 2.27(s, 6H), 2.24 (s, 3H), 2.03 (pentet, 2H, J=6.2 Hz), 1.81 (pentet, 2H,J=7.4 Hz). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acidmatrix) calcd. for C₂₃H₃₅N₅O₇S₂: 558.2 (M+H). Found: 558.0.

EXAMPLE 793-[5-Methyl-3-(2-(4-pyridylmethylaminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine

a)3-[5-Methyl-3-(2-(4-pyridylmethylaminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyphthalimide

The title compound was prepared in 97% yield from4-(aminomethyl)pyridine, in a manner analogous to step c of Eg. 68. ¹HNMR (300 MHz, CDCl₃) δ8.46 (dd, 2H, J=4.5, 1.6 Hz), 8.23 (dd, 1H, J=7.7,1.5 Hz), 8.04 (dd, 1H, J=7.7, 1.5 Hz), 7.84 (m, 2H), 7.75 (m, 3H), 7.65(td, 1H, J=7.6, 1.5 Hz), 7.16 (dd, 2H, J=4.5, 1.5 Hz), 6.64 (br s, 1H),6.62 (s, 1H), 6.59 (br s, 1H), 6.54 (t, 1H, J=2.2 Hz), 4.36 (t, 2H,J=6.1 Hz), 4.22 (d, 2H, J=6.6 Hz), 4.10 (t, 2H, J=6.1 Hz), 2.24 (s, 3H),2.17 (pentet, 2H, J=6.1 Hz).

b)3-[5-Methyl-3-(2-(4-pyridylmethylaminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyamine

The title compound was prepared in quantitative yield from3-[5-methyl-3-(2-(4-pyridylmethylaminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyphthalimide,as prepared in the previous step, in a manner analogous to step d ofExample 68, and was used without characterization.

c)3-[5-Methyl-3-(2-(4-pyridylmethylaminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine

The title compound was prepared in 78% yield from3-[5-methyl-3-(2-(4-pyridylmethylaminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyamine,as prepared in the previous step, in a manner analogous to step c ofExample 75 (without acidification with HCl-methanol). ¹H NMR (300 MHz,CDCl₃) δ8.46 (dd, 2H, J=4.5, 1.6 Hz), 8.21 (dd, 1H, J=7.8, 1.4 Hz), 8.03(dd, 1H, J=7.7, 1.4 Hz), 7.73 (td, 1H, J=7.6, 1.5 Hz), 7.64 (td, 1H,J=7.7, 1.4 Hz), 7.15 (m, 2H), 6.60 (br s, 1H), 6.58 (br s, 1H), 6.54 (t,1H, J=2.1 Hz), 4.22 (s, 2H), 3.95 (m, 4H), 2.23 (s, 3H), 2.02 (m, 2H).Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd.for C₂₂H₃₁N₅O₇S₂: 550.1 (M+H), 572.1 (M+Na). Found: 550.2, 572.1.

EXAMPLE 80N-Methyl-N-{3-[5-methyl-3-(2-(methylsulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidinehydrochloride

a)N,N′-(Bis-tert-butyloxycarbonyl)-N″-{3-[5-methyl-3-(2-(methylsulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidine

The title compound was prepared in 70% yield from2-methylsulfonylbenzenesulfonyl chloride in a manner analogous to step bof Example 19. ¹H-NMR (300 MHz, CDCl₃) δ9.08 (s, 1H), 8.45 (d, J=7.8 Hz,1H), 8.10 (d, J=7.8 Hz, 1H), 7.88 (t, J=7.7 Hz, 1H), 7.74 (t, J=7.7 Hz,1H), 7.70 (s, 1H), 6.59 (s, 2H), 6.54 (s, 1H), 4.18 (t, J=6.2 Hz, 2H),3.94 (t, J=6.1 Hz, 2H), 3.45 (s, 3H), 2.23 (s, 3H), 2.10 (pentet, J=6.2Hz, 2H), 1.49 (s, 18H).

b)N,N′-(Bis-tert-butyloxycarbonyl)-N″-methyl-N″-{3-[5-methyl-3-(2-(methylsulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidine

To a solution ofN,N′-(bis-tert-butyloxycarbonyl)-N″-{3-[5-methyl-3-(2-(methylsulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidine(220 mg, 0.334 mmol), as prepared in the preceding step,triphenylphosphine (105 mg, 0.4 mmol) and anhydrous methanol (13 mg, 17(L, 0.4 mmol) in tetrahydrofuran (5 mL) was added diethylazodicarboxylate (70 mg, 0.4 mmol). The mixture was stirred at ambientfor 4 h. After evaporated the solvent in vacuo, the residue was purifiedon a Waters Sep-Pak (10 g silica, dichloromethane to 2% ethyl acetate indichloromethane) to give the title compound as a colorless oil (100 mg,45%). ¹H-NMR (300 MHz, CDCl₃) δ8.45 (d, J=7.8 Hz, 1H), 8.13 (d, J=7.8Hz, 1H), 7.88 (t, J=7.7 Hz, 1H), 7.75 (t, J=7.7 Hz, 1H), 7.30 (s, 1H),6.60 (s, 1H), 6.59 (s, 1H), 6.58 (s, 1H), 4.17 (t, J=6.1 Hz, 2H), 3.94(t, J=6.1 Hz, 2H), 3.45 (s, 3H), 3.09 (s, 3H), 2.24 (s, 3H), 2.10(pentet, J=6.2 Hz, 2H), 1.48 (s, 9H), 1.44 (s, 9H).

c)N-Methyl-N-{3-[5-methyl-3-(2-(methylsulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidinehydrochloride

The title compound was prepared in 89% yield fromN,N′-(bis-tert-butyloxycarbonyl)-N″-methyl-N″-{3-[5-methyl-3-(2-(methylsulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidine,as prepared in the preceding step, in a manner analogous to step i ofExample 20. ¹H-NMR (300 MHz, DMSO-d₆) δ11.00 (s, 1H), 8.37 (d, J=7.8 Hz,1H), 8.13 (d, J=7.9 Hz, 1H), 8.11 (t, J=7.7 Hz, 1H), 7.96 (t, J=7.7 Hz,1H), 7.53 (br s, 3H), 6.75 (s, 1H), 6.54 (s, 1H), 6.50 (s, 1H), 3.98 (t,J=6.2 Hz, 2H), 3.87 (t, J=6.2 Hz, 2H), 3.47 (s, 3H), 2.72 (s, 3H), 2.22(s, 1H), 2.00 (pentet, J=6.3 Hz, 2H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₉H₂₅N₃O₇S₂: 472.1(M+H), 494.1 (M+Na). Found: 472.1, 494.0.

EXAMPLE 813-[3-Methyl-5-(N-methyl-2-(methylsulfonyl)phenylsulfonylamino)phenoxy]propoxyguanidinehydrochloride

a) 2-Bromo-2-methylpropanamide

To a vigorously stirred solution of 2-bromo-2-methylpropanoyl bromide(11 mL) in light petroleum ether (250 mL) at 0° C. was added in portionsaqueous ammonia (50 mL). Stirring was continued for a further 30 min.,and the resulting precipitate was collected and washed with water (2×50mL) to give the title compound as a white solid (14.1 g, 96%) which wasdirectly used for next step without further purification.

b) (3-Benzyloxy-5-methyl)phenoxy-2-methylpropanamide

3-Benzyloxy-5-methylphenol (2.14 g, 10 mmol), as prepared in step a ofExample 20, was stirred in dry 1,4-dioxane (50 mL) with sodium hydride(265 mg, 11 mmol) for 1 h. 2-Bromo-2-methylpropanamide (1.66 g, 10mmol), as prepared in step b, was added and the reaction mixture washeated to 80° C. for 6 h. After cooling , the precipitated sodiumbromide was filtered off, the filtrate was evaporated in vacuo. Theresidue was purified by flash column chromatography (7% ethyl acetate indichloromethane) to give the title compound as a pale yellow solid (2.50g, 83%). ¹H-NMR (300 MHz, CDCl₃) δ7.40 (m, 5H), 6.61 (br s, 1H), 6.54(s, 1H), 6.38 (s, 2H), 5.69 (br s, 1H), 5.29 (s, 2H), 2.28 (s, 3H), 1.97(s, 3H), 1.52 (s, 3H).

c) N-1-(3-Benzyloxy-5-methylphenyl)-2-hydroxy-2-methylpropanamide

To a solution of 2-(3-benzyloxy-5-methyl)phenoxy-2-methylpropanamide(1.50 g, 5.0 mmol), as prepared in the preceding step, in1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) (2 mL) andN,N-dimethylformamide (18 mL) was added sodium hydride (360 mg, 15mmol), the mixture was heated to 100° C. for 3 h. The solution waspoured into water (200 mL) and extracted with ethyl acetate (3×100 mL).The organic phase was washed with water (3×100 mL), dried over Na₂SO₄,and concentrated in vacuo. The residue was purified by flash columnchromatography (5% ethyl acetate in dichloromethane) to give the titlecompound as a white solid (870 mg, 58%). ¹H-NMR (300 MHz, CDCl₃) δ8.61(s, 1H), 7.42 (m, 5H), 7.28 (s, 1H), 6.93 (s, 1H), 6.59 (s, 1H), 5.05(s, 2H), 2.30 (s, 3H), 2.18 (s, 1H), 1.58 (s, 3H), 1.56 (s, 3H).

d) Benzyloxy-5-methylaniline

N-1-(3-Benzyloxy-5-methylphenyl)-2-hydroxy-2-methylpropanamide (600 mg,2.0 mmol), as prepared in the preceding step, was mixed with 10N NaOH(25 mL) and ethanol (10 mL), the mixture was heated to reflux for 2days. After cooling to ambient temperature, the mixture was diluted withwater (60 mL) and extracted with dichloromethane (3×60 mL). Thedichloromethane solution was washed with brine (2×50 mL) and dried overNa₂SO₄. After the solvent was evaporated in vacuo, the residue waspurified by flash column chromatography (dichloromethane) to give thetitle compound as a yellow oil (265 mg, 61%). ¹H-NMR (300 MHz, CDCl₃)δ7.37 (m, 5H), 6.24 (s, 1H), 6.14 (s, 2H), 5.00 (s, 2H), 3.59 (br s,2H), 2.23 (s, 3H).

e) 3-Benzyloxy-5-methyl-1-(2-(methylsulfonyl)phenylsulfonylaminobenzene

2-Methylsulfonylbenzenesulfonyl chloride (765 mg, 3.0 mmol) was added toa solution of 3-benzyloxy-5-methylaniline (640 mg, 3.0 mmol), asprepared in the preceding step, N-methylmorpholine (0.7 mL) indichloromethane (20 mL). The mixture was stirred at ambient temperatureovernight. After adding additional dichloromethane (100 mL), thedichloromethane solution was washed with saturated NaHCO₃ (2×50 mL), 10%HCl (2×50 mL), brine (2×50 mL), and dried over Na₂SO₄. After the solventwas evaporated in vacuo, the residue was purified by flash columnchromatography (3:1 dichloromethane:hexane) to give the title compoundas white solid (700 mg, 83%). ¹H-NMR (300 MHz, CDCl₃) δ8.28 (d, J=7.8Hz, 1H), 8.03 (s, 1H), 7.90 (d, J=7.8 Hz, 1H), 7.72 (t, J=7.6 Hz, 1H),7.61 (t, J=7.6 Hz, 1H), 7.38 (m, 5H), 6.69 (s, 1H), 6.65 (s, 1H), 6.48(s, 1H), 4.98 (s, 2H), 3.48 (s, 3H), 2.18 (s, 3H).

f)N-Methyl-3-benzyloxy-5-methyl-1-(2-(methylsulfonyl)phenylsulfonylaminobenzene

3-Benzyloxy-5-methyl-1-(2-(methylsulfonyl)phenylsulfonylaminobenzene(1.1 g, 2.5 mmol), as prepared in the preceding step, iodomethane (710mg, 5.0 mmol), and Cs₂CO₃ (1.65 g, 5.0 mmol) were mixed in acetonitrile(20 mL). The mixture was stirred at ambient temperature for 4 h. Thesolid was removed by filtration, the filtrate was evaporated in invacuo. The residue was dissolved in ethyl acetate (100 mL), washed withsaturated NaHCO₃ (2×50 mL), brine (2×50 mL), and dried over Na₂SO₄.After the solvent was evaporated, the residue was purified by flashcolumn chromatography (dichloromethane) to give the title compound as ayellow gum (1.08 g, 98%). ¹H-NMR (300 MHz, CDCl₃) δ8.37 (d, J=7.7 Hz,1H), 7.68 (t, J=8.1 Hz, 2H), 7.51 (t, J=8.2 Hz, 1H), 7.37 (m, 5H), 6.69(s, 1H), 6.64 (s, 1H), 6.58 (s, 1H), 4.93 (s, 2H), 3.45 (s, 3H), 3.40(s, 3H), 2.22 (s, 3H).

g) 3-Methyl-5-(N-methyl-2-(methylsulfonyl)phenylsulfonylamino)phenol

N-Methyl-3-benzyloxy-5-methyl-1-(2-(methylsulfonyl)phenylsulfonylaminobenzene(1.07 mg, 2.4 mmol) was mixed with 10% palladium on carbon (110 mg) inethanol (20 mL), the mixture was stirred under hydrogen (balloon) for 2h. the catalyst was removed by filtration through Celite, the filtratewas evaporated in vacuo to give the title compound as a pale yellow oil(680 mg, 80%) which was directly used for the next step without furtherpurification. ¹H-NMR (300 MHz, CDCl₃) δ8.38 (d, J=7.8 Hz, 1H), 7.75 (d,J=7.8 Hz, 1H), 7.72 9t, J=7.7 Hz, 1H), 7.57 (t, J=7.7 Hz, 1H), 6.55 (s,2H), 6.51 (s, 1H), 5.16 (s, 1H), 3.46 (s, 3H), 3.39 (s, 3H), 2.20 (s,3H).

h)3-{5-Methyl-3-[N-methyl-2-(methylsulfonyl)phenylsulfonylamino]phenoxy}propanol

The title compound was prepared in 91% yield from3-methyl-5-(N-methyl-(2-(methylsulfonyl)phenylsulfonylamino)phenol, asprepared in the preceding step, in a manner analogous to step b of Eg.20. ¹H-NMR (300 MHz, CDCl₃), δ8.39 (d, J=7.8 Hz, 1H), 7.72 (t, J=7.7 Hz,2H), 7.57 (t, J=7.7 Hz, 1H), 6.62 (s, 1H), 6.56 (s, 2H), 3.99 (t, J=6.0Hz, 2H), 3.81 (t, J=6.0 Hz, 2H), 3.46 (s, 3H), 3.40 (s, 3H), 2.22 (s,3H), 1.97 (pentet, J=6.0 Hz, 2H).

i)N-{3-[5-Methyl-[3-N′-methyl-(2-(methylsulfonyl)phenylsulfonylamino]phenoxy]propoxy}phthalimide

The title compound was prepared in 86% yield from3-{5-methyl-3-[N-methyl-(2-(methylsulfonyl)phenylsulfonylamino]phenoxy}propanol,as prepared in the preceding step, in a manner analogous to step d ofExample 1. ¹H-NMR (300 MHz, CDCl₃) δ8.39 (d, J=7.9 Hz, 1H), 7.85 (m,2H), 7.77 (m, 3H), 7.72 (t, J=7.7 Hz, 2H), 7.57 (t, J=7.7 Hz, 1H), 6.62(s, 1H), 3.99 (t, J=6.0 Hz, 2H), 3.81 (t, J=6.0 Hz, 2H), 3.46 (s, 3H),3.40 (s, 3H), 2.22 (s, 3H), 1.97 (pentet, J=6.0 Hz, 2H).

j)3-[5-Methyl-3-[N-methyl-(2-methylsulfonyl)phenylsulfonylamino]phenoxy]propoxyamine

The title compound was prepared in 89% yield fromN-{3-[5-methyl-[3-N-methyl-2-(methylsulfonyl)phenylsulfonylamino]phenoxy]propoxy}phthalimide,as prepared in the preceding step, in a manner analogous to step e ofExample 1. ¹H-NMR (300 MHz, CDCl₃) δ8.39 (d, J=7.9 Hz, 1H), 7.71 (t,J=7.9 Hz, 2H), 7.56 (t, J=7.8 Hz, 1H), 6.61 (s, 1H), 6.56 (s, 1H), 6.53(s, 1H), 5.39 (br s, 2H). 3.91 (t, J=6.3 Hz, 2H), 3.79 (t, J=6.1 Hz,2H), 3.46 (s, 3H), 3.40 (s, 3H), 2.12 (s, 3H), 1.99 (pentet, J=6.2 Hz,2H).

k)3-[3-Methyl-5-(N-methyl-2-(methylsulfonyl)phenylsulfonylamino)phenoxy]propoxyguanidinehydrochloride

The title compound was prepared in 85% yield from3-[5-methyl-3-[N-methyl-2-(methylsulfonyl)phenylsulfonylamino]phenoxy]propoxyamine,as prepared in the preceding step, in a manner analogous to step f ofExample 1. ¹H-NMR (300 MHz, DMSO-d₆) δ8.29 (d, J=7.8 Hz, 1H), 7.95 (t,J=7.7 Hz, 1H), 7.86 (t, J=7.7 Hz, 2H), 7.82 (t, J=7.8 Hz, 1H), 7.71 (brs, 4H), 6.71 (s, 1H), 6.63 (s, 1H), 6.59 (s, 1H), 3.98 (t, J=6.3 Hz,2H), 3.91 (t, J=6.3 Hz, 2H), 3.42 (s, 3H), 3.32 (s, 3H), 2.21 (s, 3H),2.02 (pentet, J=6.2 Hz, 2H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₉H₂₆N₄O₆S₂: 471.1(M+H), 493.1 (M+Na). Found: 471.1, 492.9.

EXAMPLE 823-[3-(2-Chlorophenylsulfonyloxy)-5-methylphenoxy]propylaminoguanidinediacetate

a) 3-[3-(2-Chlorophenylsulfonyloxy)-5-methylphenoxy]propionaldehyde

Sulfur trioxide pyridine complex (847 mg, 5.36 mmol) was added to asolution of 619 mg (1.74 mmol)3-[3-(2-chlorophenylsulfonyloxy)-5-methylphenoxy]propanol, as preparedaccording to step c of Example 1, 411 μL (3.23 mmol) ofN,N-diisopropylethylamine, and 230 μL (3.0 mmol) of dimethylsulfoxide indichloromethane (10 mL). The reaction mixture was stirred at ambienttemperature for 1 h and then quenched with 10% citric acid (20 mL). Thereaction mixture was extracted with diethyl ether (3×30 mL), dried(MgSO₄), and purified by flash chromatography (diethyl ether/petroleumether (2:1 to 4:1)) to afford 289 mg (47% yield) of the title compoundas a colorless oil. ¹H-NMR (300 MHz, CDCl₃) δ9.83 (t, 1H, J=1.4 Hz),7.97 (dd, 1H), 7.56-7.65 (m, 2H), 7.35-7.42 (m, 1H), 6.60 (br s, 1H),6.57 (br s, 1H), 6.49 (br s, 1H), 4.19 (t, 2H, J=6.1 Hz), 2.86 (dt, 2H,J=6, 1.4 Hz), and 2.25 (s, 1H).

b)2-[2-[3-(2-Chlorophenylsulfonyloxy)-5-methylphenoxy]ethyl-1-methylene]hydrazinecarboximidamidehydrochloride

A solution of 289 mg (0.82 mmol) of3-[3-(2-chlorophenylsulfonyloxy)-5-methylphenoxy]propionaldehyde, asprepared in the preceding step, 223 mg (1.62 mmol) of aminoguanidinenitrate, and 200 μL (0.80 mmol) of 4N HCl/dioxane in 3 mL of ethanol wasstirred at ambient temperature overnight. The reaction mixture wastreated with 10 mL of water and stirred for 15 min. The reaction mixturewas treated with 1.2 mL of 2N sodium hydroxide and then extracted intodichloromethane (3×20 mL). The organic phase was washed with water (3×20mL), dried (K₂CO₃), and concentrated to give 321 mg of crude product asa free base. The residue was dissolved in dichloromethane (1 mL),treated with 800 μL (3.2 mmol) of 4N HCl/dioxane solution. The solventwas removed and the product was triturated from a mixture ofdichloromethane/ether/hexane to give 190 mg of the title compound as acolorless solid. ¹H-NMR (300 MHz, DMSO-d₆) δ11.58 (br s, 1H), 7.95 (dd,1H, J=7.9, 1.5 Hz), 7.90-7.80 (m, 2H), 7.52-7.61 (m, 6H), 6.77 (s, 1H),6.49 (s, 1H), 6.46 (br t, 1H, J=2.2 Hz), 4.14 (t, 2H), 2.67 (q, 2H), and2.21 (s, 3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acidmatrix) calcd. for C₁₇H₁₉ClN₄O₄S: 411.1 (M+H). Found: 411.1.

c)[3-[3-(2-Chlorophenylsulfonyloxy)-5-methylphenoxy]propylamino]guanidinediacetate

To 300 mg of2-[2-[3-(2-chlorophenylsulfonyloxy)-5-methylphenoxy]ethyl-1-methylene]hydrazinecarboximidamidehydrochloride, as prepared in the preceding step, in tetrahydrofuran (2mL) was added 3 mL of 2N lithium borohydride in tetrahydrofuran. Thereaction mixture was stirred overnight, quenched with 2N sodiumhydroxide, and extracted into dichloromethane. The organic phase wasdried (K₂CO₃) and concentrated. The residue was dissolved indichloromethane and treated with 1 mL of glacial acetic acid. Thesolution was concentrated in vacuo. The residue was purified, togetherwith the crude product obtained from another reaction using 300 mg of2-[2-[3-(2-chlorophenylsulfonyloxy)-5-methylphenoxy]ethyl-1-methylene]hydrazinecarboximidamidehydrochloride, by flash chromatography using elutions ofdichloromethane/methanol/acetic acid (85:9.5:1.5 to 78:19:3) to give 222mg of the title compound as a gum. ¹H-NMR (300 MHz, CD₃OD) δ7.92 (dd,1H), 7.67-7.77 (m, 2H), 7.44-7.51 (ddd, 1H), 6.66-6.68 (m, 1H),6.47-6.48 (m, 2H), 3.97 (t, 2H, J=6 Hz), 2.94 (t, 2H, J=7 Hz), 2.21 (s,3H), 1.91 (pentet, 2H), 1.91 (s, 6H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₇H₂₁ClN₄O₄S: 413.1(M+H). Found: 413.1.

EXAMPLE 833-[5-Methyl-3-(2-trifluoromethylphenylsulfonyloxy)phenoxy]propylaminoguanidinehydrochloride

a) 5-Methyl-3-(2-trifluoromethylphenylsulfonyloxy)phenol

Orcinol monohydrate (2.84 g. 20.0 mmol) and2-trifluoromethylbenzenesulfonyl chloride (4.90 g, 20.0 mmol) were mixedin saturated NaHCO₃ (70 mL) and diethyl ether (70 mL). The biphasicmixture was stirred vigorously at room temperature overnight. Thereaction mixture was quenched with water (100 mL) and extracted intoethyl acetate (3×80 mL). The organic phase was washed with brine (2×50mL) and dried over Na₂SO₄. After removing the solvent in vacuo, theresidue was purified by flash column chromatography (dichloromethane to2% ethyl acetate in dichloromethane) to give the title compound as awhite solid (3.65 g, 55%). ¹H-NMR (300 MHz, CDCl₃) δ8.12 (d, J=8.0 Hz,1H), 7.98 (d, J=7.9 Hz, 1H), 7.80 (t, J=8.2 Hz, 1H), 7.69 (t, J=7.8 Hz,1H), 6.55 (s, 1H), 6.48 (s, 1H), 6.39 (s, 1H), 5.11 (s, 1H), 2.23 (s,3H).

b) 3-[5-Methyl-3-(2-trifluoromethylphenylsulfonyloxy)phenoxy]propanol

To a solution of 5-methyl-3-(2-trifluoromethylphenylsulfonyloxy)phenol(665 mg, 2.0 mmol), as prepared in the preceding step,tri-N-butylphosphine (607 mg, 3.0 mmol), and 1,3-propanediol (760 mg, 10mmol) in tetrahydrofuran (20 mL) was added1,1′-(azodicarbonyl)dipiperidine (757 mg, 3.0 mmol). The mixture wasstirred at room temperature overnight. Hexane (30 mL) was added to themixture, and the precipitates were removed by filtration. The filtratewas evaporated in vacuo and the residue was purified by flash columnchromatography (2:1 hexane/ethyl acetate) to give the title compound asa colorless oil (745 mg, 94%). ¹H-NMR (300 MHz, CDCl₃) δ8.13 (d, J=7.2Hz, 1H), 7.99 (d, J=7.2 Hz, 1H), 7.80 (t, J=7.6 Hz, 1H), 7.70 (t, J=7.3Hz, 1H), 6.63 (s, 1H), 6.48 (s, 1H), 6.46 (s, 1H), 4.02 (t, J=6.0 Hz,2H), 3.81 (m, 2H), 2.25 (s, 3H), 1.99 (m, 2H), 1.61 (s, 1H).

c)3-[5-Methyl-3-(2-trifluoromethylphenylsulfonyloxy)phenoxy]propionaldehyde

Sulfur trioxide pyridine complex (1.12 mg, 7.0 mmol) was added to asolution of3-[5-methyl-3-(2-trifluoromethylphenylsulfonyloxy)phenoxy]propanol (700mg, 1.8 mmol), as prepared in the preceding step,N,N-diisopropylethylamine (0.7 mL, 5.5 mmol), and dimethylsulfoxide (0.4mL, 5.6 mmol) in CH₂Cl₂ (20 mL). The reaction mixture was stirred at aambient temperature for 1 hour and then quenched with 10% citric acid(50 mL). The mixture was extracted into dichloromethane (3×50 mL), thenthe dichloromethane solution was washed with 10% citric acid (40 mL) anddried over Na₂SO₄. After removing the solvent in vacuo, the residue waspurified by flash column chromatography (CH₂Cl₂) to give the titlecompound as a colorless oil (595 mg, 85%). ¹H-NMR (300 MHz, CDCl₃) δ9.84(s, 1H), 8.13 (d, J=7.5 Hz, 1H), 7.99 (d, J=7.5 Hz, 1H), 7.80 (t, J=7.6Hz, 1H), 7.70 (t, J=7.3 Hz, 1H), 6.62 (s, 1H), 6.51 (s, 1H), 6.45 (s,1H), 4.21 (t, J=6.0 Hz, 2H), 2.87 (t, J=6.0 Hz, 2H), 2.25 (s, 3H).

d)2-[2-[5-Methyl-3-(2-trifluoromethylphenylsulfonyloxy)phenoxy]ethyl-1-methylene]hydrazinecarboximidamidenitrate

A solution of3-[5-methyl-3-(2-trifluoromethylphenylsulfonyloxy)phenoxy]propionaldehyde(583 mg, 1.5 mmol), as prepared in the preceding step, andaminoguanidine nitrate (412 mg, 3.0 mmol) in ethanol (10 mL) was stirredat ambient temperature overnight. Water (50 mL) was added to thereaction mixture. The precipitates were collected, washed with water(2×30 mL) and diethyl ether (2×30 mL), and dried under high vacuum togive the title compound as a colorless solid (465 mg, 61%). ¹H-NMR (300MHz, DMSO-d₆) δ8.19 (d, J=7.7 Hz, 1H), 8.11 (d, J=7.8 Hz, 1H), 8.06 (t,J=7.6 Hz, 1H), 7.94 (t, J=7.6 Hz, 1H), 7.74 (br s, 1H), 7.55 (br s, 4H),4.14 (t, J=6.3 Hz, 2H), 2.68 (t, J=9.0 Hz, 2H), 2.21 (s, 3H). Massspectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₁₈H₁₉F₃N₄O₄S: 445.1 (M+H), 467.1 (M+Na). Found: 445.0, 466.8.

e)[3-[5-Methyl-3-(2-trifluoromethylphenylsulfonyloxy)phenoxy]propylamino]guanidinehydrochloride

A mixture of2-[2-[5-methyl-3-(2-trifluoromethylphenylsulfonyloxy)phenoxy]ethyl-1-methylene]hydrazinecarboximidamidenitrate (76 mg, 0.15 mmol) and 10% palladium on carbon (10 mg) inethanol (5 mL) was stirred under hydrogen (balloon) overnight. Thecatalyst was removed by filtration through Celite. After evaporating thesolvent, the residue was dissolved in dichloromethane (50 mL), washedwith 2 N NaOH (10 mL) and brine (10 mL), and dried over K₂CO₃. Afterremoving the dichloromethane, the residue was dissolved in HCl-methanol(10 mL) and concentrated. The residue was purified by flash columnchromatography (10% methanol in dichloromethane) to give the titleproduct as a colorless foam (38 mg, 47%). ¹H-NMR (300 MHz, DMSO-d₆)δ8.90 (s, 1H), 8.19 (d, J=7.7 Hz, 1H), 8.11 (d, J=7.8 Hz, 1H), 8.06 (t,J=7.6 Hz, 1H), 7.94 (t, J=7.6 Hz, 1H), 6.90-7.70 (m, 4H), 6.76 (s, 1H),6.41 (s, 2H), 5.29 (br s, 1H), 3.99 (t, J=9.0 Hz, 2H), 2.82 (m, 2H),2.20 (s, 3H), 1.78 (m, 2H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₈H₂₁F₃N₄O₄S: 447.1(M+H). Found: 446.9.

EXAMPLE 84[3-[3-(5-Chlorothiophenyl-2-sulfonyloxy)-5-methylphenoxy]propylamino]guanidineacetate

a)3-[3-(5-Chlorothiophenyl-2-sulfonyloxy)-5-methylphenoxy]propionaldehyde

To 3-[3-(5-chlorothiophenyl-2-sulfonyloxy)-5-methylphenoxy]propanol(1.77 g, 4.88 mmol), as prepared in step b of Example 5, indichloromethane (30 mL) containing dimethylsulfoxide (760 μL, 9.08 mmol)and N,N-diisopropylethylamine (4 mL, 23 mmol) at 0° C. was added slowlysulfur trioxide pyridine complex (1.55 g, 9.8 mmol). The reactionmixture was stirred for 20 min, quenched with excess 5% citric acid(acidic to pH paper), and extracted into diethyl ether. The organicphase was washed with additional 5% citric acid, dried (MgSO₄), andpurified by flash chromatography (dichloromethane to 3% diethyl ether indichloromethane) to give 1.13 g of the title compound as an oil. ¹H-NMR(300 MHz, CDCl₃) δ9.84 (t, 1H, J=1 Hz), 7.40 (d, 1H, J=4 Hz), 6.95 (d,1H, J=4 Hz), 6.65 (br s, 1H), 6.51 (br s, 1H), 6.44 (t, 1H, J=2 Hz),4.22 (t, 2H, J=6 Hz), 2.89 (dt, 2H, J=6, 1 Hz), 2.28 (s, 3H). Massspectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₁₄H₁₃ClO₅S₂: 383.0 (M+Na). Found: 382.9

b)2-[2-[3-(5-Chlorothiophenyl-2-sulfonyloxy)-5-methylphenoxy]ethyl-1-methylene]hydrazinecarboximidamidenitrate

A mixture of3-[3-(5-chlorothiophenyl-2-sulfonyloxy)-5-methylphenoxy]propionaldehyde(1.60 g, 4.4 mmol) and aminoguanidine nitrate (0.73 g, 0.53 mmol) inethanol (15 mL) was stirred overnight at ambient temperature. Water (25mL) was added dropwise over 15 min. The mixture was stirred for 30 minthen filtered to give the title compound (1.75 g, 87%) as a white solid.¹H-NMR (300 MHz, DMSO-d₆) δ7.76 (d, 1H, J=4.2 Hz), 7.55 (t, 1H, J=5.0Hz), 7.40 (d, 1H, J=4.2 Hz), 6.81 (br s, 1H), 6.55 (br s, 1H), 6.52 (t,1H, J=2.2 Hz), 4.17 (t, 2H, J=6.4 Hz), 2.70 (dt, 2H, J=6.4, 5.0 Hz),2.26 (s, 3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acidmatrix) calcd. for C₁₅H₁₇ClN₄O₄S₂: 417.0 (M+H). Found: 416.5.

c)[3-[3-(5-Chlorothiophenyl-2-sulfonyloxy)-5-methylphenoxy]propylamino]guanidineacetate

To2-[2-[3-(5-chlorothiophenyl-2-sulfonyloxy)-5-methylphenoxy]ethyl-1-methylene]hydrazinecarboximidamidenitrate (137.5 mg, 0.29 mmol), as prepared in the preceding step, intetrahydrofuran (1 mL) was added 1 mL of 2M lithium borohydride intetrahydrofuran. The reaction mixture was stirred for 5 min, basifiedwith 10% potassium carbonate, extracted into dichloromethane, dried(K₂CO₃), and concentrated. The residue was treated with acetic acid (0.4mL) and concentrated. The residue was chromatographed using a 10 gWaters Sep-Pak silica gel column eluting withdichloromethane/methanol/acetic acid (89:9.8:1.2 to 78:19:3) to give 106mg of recovered2-[2-[3-(5-chlorothiophenyl-2-sulfonyloxy)-5-methylphenoxy]ethyl-1-methylene]hydrazinecarboximidamideacetate and 27 mg of the title compound. Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₅H₁₉ClN₄O₄S₂: 419.1(M+H). Found: 418.8.

EXAMPLE 85[3-[3-(2-Methoxyphenylsulfonyloxy)-5-methylphenoxy]propylamino]guanidinediacetate

a) 3-[3-(2-Methoxyphenylsulfonyloxy)-5-methylphenoxy]propionaldehyde

Sulfur trioxide pyridine complex (1.87 g, 11.7 mmol) was added inportions over 15 min to a solution of3-[3-(2-methoxyphenylsulfonyloxy)-5-methylphenoxy]propanol (2.07 g, 5.9mmol, prepared in step c of Example 2). N,N-diisopropylethylamine (2.15mL, 12.3 mmol), and anhydrous dimethylsulfoxide (1.25 mL, 17.6 mmol) inanhydrous dichloromethane (14 mL) at 0° C. under a nitrogen atmosphere.The solution was stirred at 0° C. for 1 h, then the reaction wasquenched with 5% aqueous citric acid (50 mL). The layers were separated,and the aqueous layer was extracted with dichloromethane (15 mL). Thecombined organic extracts were washed with 5% aqueous citric acid (50mL), pH 7 buffer (40 mL) and brine (50 mL), dried over Na₂SO₄, filtered,and evaporated. The residual gold oil was purified by flash columnchromatography (3:2 diethyl ether/hexane) to give the title compound(1.28 g, 62%) as a colorless oil. ¹H-NMR (300 MHz, CDCl₃) δ9.82 (t, 1H,J=1.5 Hz), 7.82 (dd, 1H, J=7.9, 1.7 Hz), 7.62 (ddd, 1H, J=8.4, 7.4, 1.8Hz), 7.09 (dd, 1H, J=8.4, 0.8 Hz), 7.02 (m, 1H), 6.58 (br s, 1H), 6.54(br s, 1H), 6.45 (t, 1H, J=2 Hz), 4.18 (t, 2H, J=6.1 Hz), 4.02 (s, 3H),2.85 (dt, 2H, J=6.1, 1.5 Hz), 2.24 (s, 3H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₇H₁₈O₆S: 373.1(M+Na). Found: 373.0.

b)2-[2-[3-(2-Methoxyphenylsulfonyloxy)-5-methylphenoxy]ethyl-1-methylene]hydrazinecarboximidamideacetate

A mixture of aminoguanidine hydrochloride (0.811 g, 7.33 mmol) and3-[3-(2-methoxyphenylsulfonyloxy)-5-methylphenoxy]propionaldehyde (1.28g, 3.66 mmol, prepared in the preceding step) in ethanol (30 mL) wasstirred overnight at ambient temperature. The mixture was concentratedin vacuo to approximately 15 mL, then dichloromethane (60 mL) was addedto precipitate excess aminoguanidine hydrochloride. The mixture wasfiltered and the filtrate was concentrated. The residue was dissolved indichloromethane (30 mL) and extracted with aqueous NaOH (1.85 mL of 2NNaOH in 90 mL water). The aqueous layer was extracted with CH₂Cl₂ (2×30mL). The combined organic extracts were washed with water (50 mL) andbrine (2×50 mL), dried over K₂CO₃, filtered, and evaporated to give thefree base of the title compound (1.38 g, 93%) as a gold foam.

The acetate salt of the title compound was made by adding glacial aceticacid (0.75 mL, 30 mmol) dropwise to the free base,2-[2-[3-(2-methoxyphenylsulfonyloxy)-5-methylphenoxy]-ethyl-1-methylene]hydrazinecarboximidamide,(1.03 g, 2.53 mmol, prepared above) in dichloromethane (10 mL). Solventwas removed in vacuo at ambient temperature. Crude acetate salt waspurified by flash column chromatography (20% to 100% of 1:10:40 aceticacid/methanol/dichloromethane in dichloromethane) to give the titlecompound (0.91 g, 77%) as a white foam. ¹H-NMR (300 MHz, CDCl₃) δ7.81(dd, 1H, J=7.9, 1.7 Hz), 7.62 (ddd, 1H, J=8.4, 7.5, 1.7 Hz), 7.54 (t,1H, J=5 Hz), 7.09 (d, 1H, J=8.4 Hz), 7.02 (dt, 1H, J=7.9, 0.9 Hz), 6.57(br s, 1H), 6.50 (br s, 1H), 6.46 (br s, 1H), 4.05 (t, 2H, J=6 Hz), 4.01(s, 3H), 2.68 (q, 2H, J=6 Hz), 2.23 (s, 3H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₈H₂₂N₄O₅S: 407.1(M+H). Found: 407.0.

c)[3-[3-(2-Methoxyphenylsulfonyloxy)-5-methylphenoxy]propylamino]guanidinediacetate

A solution of2-[2-[3-(2-methoxyphenylsulfonyloxy)-5-methylphenoxy]ethyl-1-methylene]hydrazinecarboximidamideacetate (239 mg, 0.522 mmol), as prepared in the preceding step, in 1 mLof THF was treated with 1.5 mL of 2M lithium borohydride in THF. Thereaction mixture was stirred overnight and quenched carefully with 10%hydrochloric acid. The reaction mixture was basified with 10% potassiumcarbonate solution, extracted into dichloromethane, dried (K₂CO₃), andconcentrated. The residue (174 mg) was treated with 500 μL of aceticacid and concentrated. Chromatography through a 10 g Waters Sep-Paksilica gel column eluting with dichloromethane/methanol/acetic acid(89:9.8:1.2) gave 102 mg of the title compound as a gum. ¹H-NMR (300MHz, DMSO-d₆) δ7.67-7.74 (m, 2H), 7.28 (d, 1H, J=8 Hz), 7.05 (dt, 1H,J=7, 1 Hz), 6.65 (br s, 1H), 6.46 (t, 1H, J=2 Hz), 6.43 (br s, 1H), 4.01(s, 3H), 3.97 (t, 2H, J=6 Hz), 2.95 (t, 2H, J=7 Hz), (s, 3H), 1.92 (s,6H), 1.90 (pentet, 2H, J=6 Hz). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₈H₂₄N₄O₅S: 409.2(M+H). Found: 408.8.

EXAMPLE 86[3-[3-(2-Cyanophenylsulfonyloxy)-5-methylphenoxy]propylamino]guanidineacetate

a) [3-(2-Cyanophenylsulfonyloxy)-5-methylphenoxy]propionaldehyde

Sulfur trioxide pyridine complex (480 mg, 3.0 mmol) was added to asolution of 3-[3-(2-cyanophenylsulfonyloxy)-5-methylphenoxy]propanol(315 mg, 0.9 mmol), as prepared in step b of Example 6,N,N-diisopropylethylamine (0.5 mL, 3.9 mmol) and dimethylsulfoxide (0.2mL. 2.8 mmol) in dichloromethane (10 mL). The reaction mixture wasstirred at ambient temperature for 1 hour and then quenched with 10%citric acid (30 mL). The mixture was extracted into dichloromethane(3×40 mL), and the dichloromethane solution was washed with 10% citricacid (30 mL) and dried over Na₂SO₄. After removing the solvent in vacuo,the residue was purified by flash column chromatography(dichloromethane) to give the title compound as a colorless oil (260 mg,83%). ¹H-NMR (300 MHz, CDCl₃) δ9.84 (s, 1H), 8.11 (m, 1H), 7.94 (m, 1H),7.78-7.81 (m, 2H), 6.65 (s, 1H), 6.61 (s, 1H), 6.57 (s, 1H), 4.24 (t,J=6.0 Hz, 2H), 2.88 (t, J=6.0 Hz, 2H), 2.27 (s, 3H).

b)[2-[3-(2-Cyanophenylsulfonyloxy)-5-methylphenoxy]ethyl-1-methylene]hydrazinecarboximidamidehydrochloride

A solution of3-[3-(2-cyanophenylsulfonyloxy)-5-methylphenoxy]propionaldehyde (240 mg,0.7 mmol), as prepared in the preceding step, and aminoguanidine nitrate(200 mg, 1.5 mmol) in ethanol (8 mL) was stirred at ambient temperatureovernight. Water (20 mL was added to the reaction mixture. Theprecipitates were collected, washed with water (2×15 mL) and diethylether (2×20 mL), and dried under high vacuum. The solid was suspended inwater (40 mL), treated with 2N sodium hydroxide (1.0 mL), and extractedinto dichloromethane (3×50 mL). The organic phase was dried over K₂CO₃.After removing the solvent, the residue was dissolved in dichloromethane(1 mL), and the dichloromethane solution was added to the solution of1.5 mL of 0.6M HCl methanol in diethyl ether (50 mL) to give the titlecompound as a colorless solid (245 mg, 80%). ¹H-NMR (300 MHz, DMSO-d₆)δ8.28 (m, 1H), 8.09 (m, 1H), 7.97-8.04 (m, 2H), 7.55 (br s, 5H), 6.80(s, 1H), 6.50 (s, 2H), 4.15 (t, J=6.3 Hz, 2H), 2.68 (m, 2H), 2.22 (s,3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix)calcd. for C₁₈H₁₉N₅O₄S: 402.1 (M+H), 424.1 (M+Na), 440.1 (M+K). Found:402.1, 424.1, 440.1.

c) -[3-(2-Cyanophenylsulfonyloxy)-5-methylphenoxy]propylamino]guanidineacetate

To a suspension of2-[2-[3-(2-cyanophenylsulfonyloxy)-5-methylphenoxy]ethyl-1-methylene]hydrazinecarboximidamidehydrochloride (190 mg, 0.4 mmol), prepared in the preceding step, intetrahydrofuran (5 mL) was added lithium borohydride (2M, 3.0 mL. 6.0mmol). The reaction mixture was stirred at ambient temperature for twodays under nitrogen. The solution was acidified (pH 2) with 10% HClsolution, and the mixture was stirred for 10 minutes. The solution wasbasified (pH 8-9) with 2N NaOH, and the mixture was extracted withdichloromethane (3×50 mL). The dichloromethane extracts were washed withbrine (50 mL) and dried over K₂CO₃. After removing the solvent, theresidue was purified by flash column chromatography (90:9:1dichloromethane/methanol/acetic acid) to give the title compound as acolorless gum (65 mg, 35%). ¹H-NMR (300 MHz, CDCl₃) δ8.30 (br s, 2H),7.94-8.11 (m, 4H), 6.78 (s, 1H), 6.49 (s, 1H), 6.43 (s, 1H), 4.09 (t,J=8.0 Hz, 2H), 2.75 (t, J=6.7 Hz, 2H), 2.22 (s, 3H), 1.78 (m, 2H). Massspectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₁₈H₂₁N₅O₄S: 404.1 (M+H). Found: 404.5.

EXAMPLE 87 In vitro Inhibition of Purified Enzymes

Reagents

All buffer salts were obtained from Sigma Chemical Company (St. Louis,Mo.), and were of the highest purity available. The enzyme substrates,N-benzoyl-Phe-Val-Arg-p-nitroanilide (Sigma B7632),N-benzoyl-Ile-Glu-Gly-Arg-p-nitroanilide hydrochloride (Sigma B2291),N-p-Tosyl-Gly-Pro-Lys-p-nitroanilide (Sigma T6140),N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide (Sigma S7388) andN-CBZ-Val-Gly-Arg-p-nitroanilide (Sigma C7271) were obtained from Sigma.N-succinyl-Ala-Ala-Pro-Arg-p-nitroanilide (BACHEM L-1720) andN-succinyl-Ala-Ala-Pro-Val-p-nitroanilide (BACHEM L-1770) were obtainedfrom BACHEM (King of Prussia, Pa.).

Human α-thrombin, human factor Xa and human plasmin were obtained fromEnzyme Research Laboratories (South Bend, Ind.). Bovine α-chymotrypsin(Sigma C4129), bovine trypsin (Sigma T8642) and human kidney cellurokinase (Sigma U5004) were obtained from Sigma. Human leukocyteelastase was obtained from Elastin Products (Pacific, Mo.).

K_(i) Determinations

All assays are based on the ability of the test compound to inhibit theenzyme catalyzed hydrolysis of a peptide p-nitroanilide substrate. In atypical K_(i) determination, substrate is prepared in DMSO, and dilutedinto an assay buffer consisting of 50 mM HEPES, 200 mM NaCl, pH 7.5. Thefinal concentrations for each of the substrates is listed below. Ingeneral, substrate concentrations are lower than the experimentallydetermined value for K_(m). Test compounds are prepared as a 1.0 mg/mlsolution in DMSO. Dilutions are prepared in DMSO yielding 8 finalconcentrations encompassing a 200 fold concentration range. Enzymesolutions are prepared at the concentrations listed below in assaybuffer.

In a typical K_(i) determination, into each well of a 96 well plate ispipetted 280 μL of substrate solution, 10 μL of test compound solution,and the plate allowed to thermally equilibrate at 37° C. in a MolecularDevices plate reader for >15 minutes. Reactions were initiated by theaddition of a 10 μL aliquot of enzyme and the absorbance increase at 405nm is recorded for 15 minutes. Data corresponding to less than 10% ofthe total substrate hydrolysis were used in the calculations. The ratioof the velocity (rate of change in absorbance as a function of time) fora sample containing no test compound is divided by the velocity of asample containing test compound, and is plotted as a function of testcompound concentration. The data are fit to a linear regression, and thevalue of the slope of the line calculated. The inverse of the slope isthe experimentally determined K_(i) value.

Thrombin

Thrombin activity was assessed as the ability to hydrolyze the substrateN-succinyl-Ala-Ala-Pro-Arg-p-nitroanilide. Substrate solutions wereprepared at a concentration of 32 μM (32 μM<<Km=180 μM) in assay buffer.Final DMSO concentration was 4.3%. Purified human α-thrombin was dilutedinto assay buffer to a concentration of 15 nM. Final reagentconcentrations were: [thrombin]=0.5 nM, [substrateN-succinyl-Ala-Ala-Pro-Arg-p-nitroanilide]=32 μM.

Factor X [FXa]

FXa activity was assessed as the ability to hydrolyze the substrateN-benzoyl-Ile-Glu-Gly-Arg-p-nitroanilide hydrochloride. Substratesolutions were prepared at a concentration of 51 μM (51<<K_(m)=1.3 mM)in assay buffer. Final DMSO concentration was 4.3%. Purified activatedhuman Factor X was diluted into assay buffer to a concentration of 300nM. Final reagent concentrations were: [FXa]=10 nM,[N-benzoyl-Ile-Glu-Gly-Arg-p-nitroanilide hydrochloride]=51 μM.

Plasmin

Plasmin activity was assessed as the ability to hydrolyze theN-p-Tosyl-Gly-Pro-Lys-p-nitroanilide. Substrate solutions were preparedat a concentration of 37 μM (37 μM<<K_(m)=243 μM) in assay buffer. FinalDMSO concentration was 4.3%. Purified human plasmin was diluted intoassay buffer to a concentration of 240 nM. Final reagent concentrationswere: [Plasmin]=8 nM, [N-p-Tosyl-Gly-Pro-Lys-p-nitroanilide]=37 μM.

Chymotrypsin

Chymotrypsin activity was assessed as the ability to hydrolyzeN-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide. Substrate solutions wereprepared at a concentration of 14 μM (14 μM<<K_(m)=62 μM) in assaybuffer. Final DMSO concentration was 4.3%. Purified bovine chymotrypsinwas diluted into assay buffer to a concentration of 81 nM. Final reagentconcentrations were: [Chymotrypsin]=2.7 nM,[N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide]=14 μM.

Trypsin

Trypsin activity was assessed as the ability to hydrolyzeN-benzoyl-Phe-Val-Arg-p-nitroanilide. Substrate solutions were preparedat a concentration of 13 μM (13 μM<<K_(m)=291 μM) in assay buffer. FinalDMSO concentration was 4.3%. Purified bovine trypsin was diluted intoassay buffer to a concentration of 120 nM. Final reagent concentrationswere: [Trypsin]=4 nM, [N-benzoyl-Phe-Val-Arg-p-nitroanilide]=13 μM.

Elastase

Elastase activity was assessed as the ability to hydrolyzeN-succinyl-Ala-Ala-Pro-Val-p-nitroanilide. Substrate solutions wereprepared at a concentration of 19 μM (19 μM<<K_(m)=89 μM) in assaybuffer. Final DMSO concentration was 4.3%. Purified human leukocyteelastase was diluted into assay buffer to a concentration of 750 nM.Final reagent concentrations were: [Elastase]=25 nM,[N-succinyl-Ala-Ala-Pro-Val-p-nitroanilide]=19 μM.

Urokinase

Urokinase activity was assessed as the ability to hydrolyzeN-CBZ-Val-Gly-Arg-p-nitroanilide. Substrate solutions were prepared at aconcentration of 100 μM (100 μM<K_(m)=1.2 mM) in assay buffer. FinalDMSO concentration was 4.3%. Purified human kidney urokinase was dilutedinto assay buffer to a concentration of 1.2 μM. Final reagentconcentrations were: [Urokinase]=40 nM, andN-CBZ-Val-Gly-Arg-p-nitroanilide]=100 mM.

The results of the compounds of Examples 1, 2, 3, 8, 11, 82 and 83 areshown in the following table.

TABLE 1 Assay, K_(i)(nM) or (% inhibition at [nM]) Compound (Eg. No.)Thrombin FXa Chymotrypsin Elastase Plasmin Trypsin 82 2.6 45000 (0% at12500) (0% at 12500) (0% at 12500) 36000 83 7.2 (0% at 1400) (0% at1400) (0% at 1400) (0% at 1400) (0% at 1400) 1 7.5 (0% at 13300) (0% at13300) (0% at 13300) (0% at 13300) 37000 2 10 (0% at 2600) (0% at 2600)(0% at 2600) (0% at 2600) (0% at 2600) 3 7 (0% at 21870) (0% at 21870)(0% at 21870) (0% at 21870) 21000 8 10 (0% at 22490) (0% at 22490) (0%at 22490) (0% at 22490) 25000 11 11 (0% at 21360) (0% at 21360) (0% at21360) (0% at 21360) (0% at 21360)

The results indicate that the compounds of the present invention areinhibitors of proteases, including thrombin. In addition, the compoundsof Examples 1, 2, 3, 8, 11, 82 and 83 are potent and highly selectiveinhibitors of thrombin.

Having now fully described this invention, it will be understood tothose of ordinary skill in the art that the same can be performed withina wide and equivalent range of conditions, formulations, and otherparameters without affecting the scope of the invention or anyembodiment thereof. All patents and publications cited herein are fullyincorporated by reference herein in their entirety.

What is claimed is:
 1. A compound having the Formula I:

or a solvate, hydrate or pharmaceutically acceptable salt thereof;wherein: R¹ is one of C₃₋₈ alkyl, cycloalkyl, alkenyl, alkynyl, aryl,aralkyl, any of which may be optionally substituted; Z is —OSO₂— or—SO₂O—; R^(y) and R^(z) are each independently one of hydrogen, alkyl,cycloalkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl,monoalkylaminoalkyl, dialkylaminoalkyl or carboxy; R², R³ and R⁴ areeach independently one of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl,aryl, aralkyl, trifluoromethyl, halogen, hydroxyalkyl, cyano, nitro,carboxamido, —CO₂R^(x), —CH₂OR^(x) or —OR^(x), or when present onadjacent carbon atoms, R² and R³ may also be taken together to form oneof —CH═CH—CH═CH— or —(CH₂)_(q)—, where q is from 2 to 6, and R⁴ isdefined as above; R^(x), in each instance, is independently one ofhydrogen, alkyl or cycloalkyl wherein said alkyl or cycloalkyl groupsmay optionally have one or more unsaturations; Y is one of —O—, —NR¹⁰—,—S—, —CHR¹⁰— or a covalent bond; X is oxygen or NR⁹; R⁹ is one ofhydrogen, alkyl, cycloalkyl or aryl, wherein said alkyl, cycloalkyl oraryl can be optionally substituted with amino, monoalkylamino,dialkylamino, alkoxy, hydroxy, carboxy, alkoxycarbonyl, aryloxycarbonyl,aralkoxycarbonyl, aryl, acylamino, cyano or trifluoromethyl; R⁶ is oneof hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl,monoalkylamino(C₂₋₁₀)alkyl, dialkylamino(C₂₋₁₀)alkyl or carboxyalkyl; orR⁶ and R¹² are taken together to form —(CH₂)_(w)—, where w is 1-5; R⁷ isone of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl,monoalkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, hydroxy, alkoxy,aralkoxy, aryloxy, or mono- or di-alkylamino, provided that n is otherthan zero when R⁷ is hydroxy, alkoxy, aralkoxy, aryloxy, or mono- ordi-alkylamino; R⁸, R¹¹ and R¹² are each independently one of hydrogen,alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl,dialkylaminoalkyl or carboxyalkyl; or R⁷ and R⁸ are taken together toform —(CH₂)_(y)—, where y is zero (a bond), 1 or 2, while R¹¹ and R¹²are defined as above; or R⁷ and R¹² are taken together to form—(CH₂)_(q)—, where q is zero (a bond), or 1 to 8, while R⁸ and R¹¹ aredefined as above; or R⁸ and R¹¹ are taken together to form —(CH₂)_(r)—,where r is 2-8, while R⁷ and R¹² are defined as above; R¹⁰, in eachinstance, is independently one of hydrogen, alkyl, aralkyl, aryl,hydroxyalkyl, aminoalkyl, monoalkylamino(C₂₋₁₀)alkyl,dialkylamino(C₂₋₁₀)alkyl or carboxyalkyl; R^(a), R^(b) and R^(c) areindependently hydrogen, alkyl, hydroxy, alkoxy, aryloxy, aralkoxy,alkoxycarbonyloxy, cyano or —CO₂R^(w); R^(w) is alkyl, cycloalkyl,phenyl, benzyl,

where R^(d) and R^(e) are independently hydrogen, C₁₋₆ alkyl, C₂₋₆alkenyl or phenyl, R^(f) is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl orphenyl, R^(g) is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl or phenyl, and R^(h)is aralkyl or C₁₋₆ alkyl; n is from zero to 8; and m is from zero to 4.2. A compound of claim 1, wherein R¹ is one of C₃₋₈ alkyl, C₄₋₇cycloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl or C₆₋₄ aryl, any of which isoptionally substituted.
 3. A compound of claim 1, wherein R¹ is one ofC₃₋₈ alkyl, C₄₋₇ cycloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl or C₆₋₁₄ aryl,any of which is optionally substituted by one or two moietiesindependently selected from the group consisting of alkyl, hydroxy,nitro, trifluoromethyl, halogen, alkoxy, aminoalkoxy, aminoalkyl,hydroxyalkyl, hydroxyalkoxy, cyano, aryl, amino, monoalkylamino,dialkylamino, carboxy, carboxyalkyl, carboxyalkoxy,mono(hydroxyalkyl)amino, bis(hydroxyalkyl)amino,mono(carboxyalkyl)amino, bis(carboxyalkyl)amino, alkoxycarbonylamino,alkoxycarbonyl, aralkoxycarbonyl, alkenylcarbonyl, alkynylcarbonyl,alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl,aralkylsulfonyl, alkylsulfinyl, alkylsulfonamido, arylsulfonamido,aralkylsulfonamido, amidino, guanidino, alkyliminoamino,formyliminoamino, trifluoromethoxy, perfluoroethoxy and R¹³R¹⁴NSO₂—,where R¹³ and R¹⁴ are independently selected from the group consistingof hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl,carboxyalkyl, alkoxycarbonylalkyl, cyanoalkyl, hydroxyalkyl,alkoxyalkyl, mono- and di-alkylaminoalkyl.
 4. A compound of claim 1,wherein Y is one of —O—, —NR¹⁰— or a covalent bond, and R¹⁰ in eachinstance is one of hydrogen, C₁₋₆alkyl, benzyl, phenethyl,C₂₋₁₀hydroxyalkyl or C₂₋₇carboxyalkyl.
 5. A compound of claim 4, whereinY is —O—.
 6. A compound of claim 1, wherein Z is —SO₂O—.
 7. A compoundof claim 1, wherein R^(a), R^(b) and R^(c) are hydrogen.
 8. A compoundof claim 1, wherein R⁷ and R⁸ and R¹¹ and R¹² are independentlyhydrogen, C₁₋₆alkyl, C₆₋₁₀ar(C₁₋₆)alkyl, C₆₋₁₀aryl, C₂₋₁₀hydroxyalkyl orC₂₋₁₀ carboxyalkyl.
 9. A compound of claim 1, wherein R⁷ and R⁸ aretaken together to form —(CH₂)_(y)—, and y is 0, 1 or
 2. 10. A compoundof claim 1, wherein n is from 1 to
 4. 11. A compound of claim 1, whereinm is zero, 1, 2 or
 3. 12. A compound of claim 1, wherein m and n areeach zero and R⁷, R⁸, R¹¹ and R¹² are each hydrogen.
 13. A compound ofclaim 1, wherein R² and R⁴ are hydrogen and R³ is methyl.
 14. A compoundof claim 1, wherein: R¹ is C₆₋₁₀ aryl which is optionally substituted byone or two of hydroxy, nitro, trifluoromethyl, halogen, C₁₋₆ alkyl,C₆₋₁₀ aryl, C₁₋₆ alkoxy, C₆₋₁₀ ar(C₁₋₆)alkoxy, C₁₋₆ aminoalkyl, C₁₋₆aminoalkoxy, amino, mono(C₁₋₄)alkylamino, di(C₁₋₄)alkylamino, C₂₋₆alkoxycarbonylamino, C₂₋₆ alkoxycarbonyl, carboxy, C₁₋₆ hydroxyalkyl,C₂₋₆ hydroxyalkoxy, (C₁₋₆)alkoxy(C₂₋₆)alkoxy, mono- and di-C₁₋₄alkylamino(C₂₋₆)alkoxy, C₂₋₁₀ mono(carboxyalkyl)amino, bis(C₂₋₁₀carboxyalkyl)amino, C₆₋₁₄ ar(C₁₋₆)alkoxycarbonyl, C₂₋₆ alkynylcarbonyl,C₁₋₆ alkylsulfonyl, C₂₋₆ alkenylsulfonyl, C₂₋₆ alkynylsulfonyl, C₆₋₁₀arylsulfonyl, C₆₋₁₀ ar(C₁₋₆) alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonamido, C₆₋₁₀ arylsulfonamido, C₆₋₁₀ ar(C₁₋₆)alkylsulfonamido, amidino, guanidino, C₁₋₆ alkyliminoamino,formyliminoamino, C₂₋₆ carboxyalkoxy, C₂₋₆ carboxyalkyl,carboxyalkylamino, cyano, trifluoromethoxy, perfluoroethoxy andR¹³R¹⁴NSO₂—; R¹³ and R¹⁴ are independently selected from the groupconsisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl,aralkyl, carboxyalkyl, alkoxycarbonylalkyl, cyano(C₂₋₁₀)alkyl,hydroxy(C₂₋₁₀)alkyl, alkoxy(C₂₋₁₀)alkyl, mono- anddi-alkylamino(C₂₋₁₀)alkyl; Z is —SO₂O—; R², R³ and R⁴ are independentlyone of hydrogen, C₁₋₄ alkyl, C₃₋₈ cycloalkyl, phenyl, benzyl,trifluoromethyl, halogen, hydroxy(C₁₋₄)alkyl, cyano, nitro, carboxamido,carboxy, C₁₋₄ alkoxycarbonyl, C₁₋₄ alkoxymethyl or C₁₋₄ alkoxy; oralternatively, R² and R³, when present on adjacent carbon atoms, mayalso be taken together to form one of—CH═CH—CH═CH— or —(CH₂)_(q)—, whereq is from 2 to 6, and R⁴ is as defined above; Y is one of —O—, —S—,—NR¹⁰—, or a covalent bond; R^(a), R^(b) and R^(c) are each one ofhydrogen, C₁₋₄ alkyl, hydroxy, C₁₋₄ alkoxy, phenoxy, C₁₋₄alkyloxycarbonyl, benzyloxycarbonyl, cyano,

where R^(h) is benzyl, methyl, ethyl, isopropyl, sec-butyl or t-butyl,and where R^(f) is hydrogen or C₁₋₆ alkyl; R⁶ is one of hydrogen, C₁₋₆alkyl, C₆₋₁₀ ar(C₁₋₆)alkyl, C₆₋₁₀ aryl, C₂₋₁₀ hydroxyalkyl, C₂₋₁₀aminoalkyl, mono(C₁₋₄)alkylamino(C₂₋₈)alkyl,di(C₁₋₄)alkylamino(C₂₋₈)alkyl or C₂₋₁₀ carboxyalkyl; R⁷, R⁸, R¹¹ and R¹²are independently one of hydrogen, C₁₋₆ alkyl, C₂₋₁₀ carboxyalkyl orC₂₋₁₀ hydroxyalkyl, or R⁷ and R⁸ are taken together to form —(CH₂)_(y)—where y is zero, 1 or 2, while R¹¹ and R¹² are defined as above; or R⁷and R¹² are taken together to form —(CH₂)_(q)—, where q is zero (abond), or 1, 2 or 3, while R⁸ and R¹¹ are defined as above; or R⁸ andR¹¹ are taken together to form —(CH₂)_(r)—, where r is 2, 3, or 4, whileR⁷ and R¹² are defined as above; R⁹ is hydrogen, or C₁₋₁₀ alkyl,optionally substituted with amino, mono(C₁₋₄)alkylamino, C₁₋₆ alkoxy,hydroxy, carboxy, phenyl, C₁₋₄ alkyloxycarbonyl, C₆₋₁₀ar(C₁₋₄)alkoxycarbonyl, C₁₋₆ acylamino, cyano or trifluoromethyl; R¹⁰,in each instance, is independently hydrogen, C₁₋₆ alkyl, benzyl, phenyl,C₂₋₁₀ hydroxyalkyl, C₂₋₁₀ aminoalkyl, C₁₋₄ monoalkylamino(C₂₋₈)alkyl,C₁₋₄ dialkylamino(C₂₋₈)alkyl or C₂₋₁₀ carboxyalkyl; n is from zero to 8;and m is from zero to
 4. 15. A compound of claim 1, wherein: R¹ isphenyl or naphthyl, optionally substituted by one or two of chloro,methoxy, methyl, trifluoromethyl, cyano, nitro, amino or dimethylamino;Z is —SO₂O—; R² and R³ are hydrogen or C₁₋₄ alkyl, or R² and R³ may alsobe taken together to form —CH═CH—CH═CH—; R⁴ is one hydrogen, methyl,methoxy or trifluoromethyl; Y is one of O, NR¹⁰ or a covalent bond;R^(a), R^(b) and R^(c) are hydrogen, hydroxy,

where R^(h) is benzyl or t-butyl, and where R^(f) is hydrogen or methyl;R⁶ is hydrogen, C₁₋₄ alkyl, C₂₋₄ hydroxyalkyl, C₂₋₄ carboxyalkyl, C₂₋₄aminoalkyl, dimethylamino(C₂₋₈)alkyl, or methylamino(C₂₋₈)alkyl; R⁷, R⁸,R¹¹ and R¹² are independently one of hydrogen, C₁₋₆ alkyl, C₂₋₁₀hydroxyalkyl or C₂₋₁₀ carboxyalkyl, or R⁷ and R⁸ are taken together toform —(CH₂)_(y)— where y is zero, 1 or 2, while R¹¹ and R¹² are definedas above; or R⁷ and R¹² are taken together to form —(CH₂)_(q)—, where qis zero (a bond), or 1, 2 or 3, while R⁸ and R¹¹ are defined as above;or R⁸ and R¹¹ are taken together to form —(CH₂)_(r)—, where r is 2, 3 or4, while R⁷ and R¹² are defined as above; R⁹ is hydrogen or C₁₋₄ alkyl;R¹⁰, in each instance, is independently hydrogen, C₁₋₄ alkyl, C₂₋₄hydroxyalkyl, C₂₋₄ carboxyalkyl, C₂₋₄ aminoalkyl,dimethylamino(C₂₋₈)alkyl, methylamino(C₂₋₈)alkyl; n is from zero to 4;and m is zero, 1, 2 or
 3. 16. A compound of claim 1, wherein: R¹ isphenyl, substituted by C₁₋₆ alkylsulfonyl, C₆₋₁₀ arylsulfonyl, C₆₋₁₀ar(C₁₋₆)alkylsulfonyl, C₆₋₁₀ arylsulfonamido, C₆₋₁₀ar(C₁₋₆)alkylsulfonamido, or R¹³R¹⁴NSO₂—, where R¹³ and R¹⁴ areindependently selected from the group consisting of hydrogen, C₁₋₆alkyl, C₃₋₇ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₆₋₁₀ar(C₁₋₄)alkyl, carboxy(C₁₋₆)alkyl, C₁₋₄ alkoxycarbonyl(C₁₋₄)alkyl,cyano(C₂₋₆)alkyl, hydroxy(C₂₋₆)alkyl, C₁₋₄alkoxy(C₂₋₆)alkyl, mono- anddi-(C₁₋₄)alkylamino(C₂₋₆)alkyl; Z is one of —SO₂O—, —SO₂NR¹⁰—, —CH₂O— or—OCH₂—; R² and R³ are hydrogen of C₁₋₄ alkyl, or R² and R³ may also betaken together to form —CH═CH—CH═CH—, R⁴ is one of hydrogen, methyl,methoxy or trifluoromethyl; Y is one of O, NR¹⁰ or a covalent bond; R¹,R^(b) and R^(c) are hydrogen, hydroxy,

where R^(h) is benzyl or t-butyl, and where R^(f) is hydrogen or methyl;R⁶ is hydrogen, C₁₋₄ alkyl, C₂₋₄ hydroxyalkyl, C₂₋₄ carboxyalkyl, C₂₋₄aminoalkyl, dimethylamino(C₂₋₈)alkyl, or methylamino(C₂₋₈)alkyl; R⁷, R⁸,R¹¹ and R¹² are independently one of hydrogen, C₁₋₆ alkyl, C₂₋₁₀hydroxyalkyl or C₂₋₁₀ carboxyalkyl, or R⁷ and R⁸ are taken together toform —(CH₂)_(y)— where y is zero, 1 or 2, while R¹¹ and R¹² are definedas above; or R⁷ and R¹² are taken together to form —(CH₂)_(q)—, where qis zero (a bond), or 1, 2 or 3, while R⁸ and R¹¹ are defined as above;or R⁸ and R¹¹ are taken together to form —(CH₂)_(r)—, where r is 2, 3 or4, while R⁷ and R¹² are defined as above; R⁹ is hydrogen or C₁₋₄ alkyl;R¹⁰, in each instance, is independently hydrogen, C₁₋₄ alkyl, C₂₋₄hydroxyalkyl, C₂₋₄ carboxyalkyl, C₂₋₄ aminoalkyl,dimethylamino(C₂₋₈)alkyl, methylamino(C₂₋₈)alkyl; n is from zero to 4;and m is zero, 1, 2 or
 3. 17. A compound of claim 1, wherein the moiety—Z—R¹ is attached to the benzene ring in a position meta- to Y.
 18. Acompound of claim 1, wherein: R¹ is phenyl, substituted by C₁₋₆alkylsulfonyl, C₆₋₁₀ arylsulfonyl, C₆₋₁₀ ar(C₁₋₆)alkylsulfonyl, C₆₋₁₀arylsulfonamido, C₆₋₁₀ ar(C₁₋₆)alkylsulfonamido, or R¹³R¹⁴NSO₂—, whereR¹³ and R¹⁴ are independently selected from the group consisting ofhydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₆₋₁₀ ar(C₁₋₄)alkyl, carboxy(C₁₋₆)alkyl, C₁₋₄alkoxycarbonyl(C₁₋₄)alkyl, cyano(C₂₋₆)alkyl, hydroxy(C₂₋₆)alkyl,C₁₋₄alkoxy(C₂₋₆)alkyl, mono- and di-(C₁₋₄)alkylamino(C₂₋₆)alkyl; Z is—SO₂O—; R² and R³ are hydrogen or C₁₋₄ alkyl, or R² and R³ may also betaken together to form —CH═CH—CH═CH—; R⁴ is one of hydrogen, methyl,methoxy or trifluoromethyl; Y is one of O, NR¹⁰ or a covalent bond;R^(a), R^(b) and R^(c) are hydrogen, hydroxy,

where R^(h) is benzyl or t-butyl, and where R^(f) is hydrogen or methyl;R⁶ is hydrogen, C₁₋₄ alkyl, C₂₋₄ hydroxyalkyl, C₂₋₄ carboxyalkyl, C₂₋₄aminoalkyl, dimethylamino(C₂₋₈)alkyl, or methylamino(C₂₋₈)alkyl; R⁷, R⁸,R¹¹ and R¹² are independently one of hydrogen, C₁₋₆ alkyl, C₂₋₁₀hydroxyalkyl or C₂₋₁₀ carboxyalkyl, or R⁷ and R⁸ are taken together toform —(CH₂)_(y)— where y is zero, 1 or 2, while R¹¹ and R¹² are definedas above; or R⁷ and R¹² are taken together to form —(CH₂)_(q)—, where qis zero (a bond), or 1, 2 or 3, while R⁸ and R¹¹ are defined as above;or R⁸ and R¹¹ are taken together to form —(CH₂)_(r)—, where r is 2, 3 or4, while R⁷ and R¹² are defined as above; R⁹ is hydrogen or C₁₋₄ alkyl;R¹⁰, in each instance, is independently hydrogen, C₁₋₄ alkyl, C₂₋₄hydroxyalkyl, C₂₋₄ carboxyalkyl, C₂₋₄ aminoalkyl,dimethylamino(C₂₋₈)alkyl, methylamino(C₂₋₈)alkyl; n is from zero to 4;and m is zero, 1, 2 or
 3. 19. A compound of claim 18, wherein: R²⁴ ismethyl; Y′ is O; a is one; and X′ is O or NH.
 20. A compound having theformula:

or a solvate, hydrate, pharmaceutically acceptable salt or prodrugthereof, wherein R²¹ is phenyl or naphthyl, optionally substituted byone or two substituents independently selected from the group consistingof halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, methoxy, trifluoromethyl, cyano,nitro, amino or dimethylamino; and when R²¹ is phenyl, said phenyl canbe optionally substituted by C₁₋₆ alkylsulfonyl, C₆₋₁₀ arylsulfonyl,C₆₋₁₀ ar(C₁₋₆)alkylsulfonyl, C₆₋₁₀ arylsulfonamido, C₆₋₁₀ ar(C₁₋₆)alkylsulfonamido, or R²²R²³NSO₂—, where R²² and R²³ are independentlyselected from the group consisting of hydrogen, C₁₋₆ alkyl, C₃₋₇cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₆₋₁₀ ar(C₁₋₄)alkyl,carboxy(C₁₋₆)alkyl, C₁₋₄ alkoxycarbonyl(C₁₋₄)alkyl, cyano(C₂₋₆)alkyl,hydroxy(C₂₋₆)alkyl, C₁₋₄ alkoxy(C₂₋₆)alkyl, mono- anddi-(C₁₋₄)alkylamino(C₂₋₆)alkyl; R²⁴ is hydrogen or C₁₋₄ alkyl; X′ is Oor NR²⁹; and R²⁹ is hydrogen or C₁₋₄ alkyl; Y′ is one of O, NR¹⁰ or acovalent bond, wherein R¹⁰ is hydrogen, C₁₋₆ alkyl, C₆₋₁₀ ar(C₁₋₆)alkyl,C₆₋₁₀ aryl, C₂₋₁₀ hydroxyalkyl C₂₋₁₀ aminoalkyl, C₂₋₇ carboxyalkyl,mono(C₁₋₄ alkyl)amino(C₁₋₈)alkyl, and di(C₁₋₄ alkyl)amino(C₁₋₈)alkyl;and b is 0, 1 or
 2. 21. A compound of claim 1, which is one of3-[3-(2-chlorophenylsulfonyloxy)-5-methylphenoxy]propoxyguanidine;3-[3-(2-methoxyphenylsulfonyloxy)-5-methylphenoxy]propoxyguanidine;3-[3-(5-chloro-2-methoxyphenylsulfonyloxy)-5-methylphenoxy]propoxyguanidinehydrochloride;3-[5-methyl-3-[2-(methylsulfonyl)phenylsulfonyloxy]phenoxy]propoxyguanidinehydrochloride;1-[[5-methyl-3-(2-methylsulfonylphenylsulfonyloxy)phenoxy]methyl]cyclopropylmethoxyguanidinehydrochloride; 3-[5-methyl-3-(2-phenylsulfonyl)phenoxy]propoxyguanidinehydrochloride;3-[5-methyl-3-(2-(N-(2-ethoxycarbonylethyl)-N-benzylaminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinehydrochloride;3-[5-methyl-3-(-2-(N-benzyl-N-(2-(N,N-dimethylamino)ethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidinedihydrochloride; or a hydrochloride or acetate salt thereof.
 22. Acompound having the Formula I:

or a solvate, hydrate or pharmaceutically acceptable salt thereof;wherein: R¹ is one of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, oraralkyl, any of which may be optionally substituted; Z is —OSO₂— or—SO₂O—; R^(y) and R^(z) are each independently one of hydrogen, alkyl,cycloalkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl,monoalkylaminoalkyl, dialkylaminoalkyl or carboxy; R², R³ and R⁴ areeach independently one of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl,aryl, aralkyl, trifluoromethyl, halogen, hydroxyalkyl, cyano, nitro,carboxamido, —CO₂R^(x), —CH₂OR^(x) or —OR^(x), or when present onadjacent carbon atoms, R² and R³ may also be taken together to form oneof —CH═CH—CH═CH— or —(CH₂)_(q)—, where q is from 2 to 6, and R⁴ isdefined as above; R^(x), in each instance, is independently one ofhydrogen, alkyl or cycloalkyl wherein said alkyl or cycloalkyl groupsmay optionally have one or more unsaturations; Y is one of —O—, —NR¹⁰—,—S—, —CHR¹⁰— or a covalent bond; R¹⁰, in each instance, is independentlyone of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl,monoalkylamino(C₂₋₁₀)alkyl, dialkylamino(C₂₋₁₀)alkyl or carboxyalkyl;R^(w) is alkyl, cycloalkyl, phenyl, benzyl,

where R^(d) and R^(e) are independently hydrogen, C₁₋₆ alkyl, C₂₋₆alkenyl or phenyl, R^(f) is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl orphenyl, R^(g) is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl or phenyl, and R^(h)is aralkyl or C₁₋₆ alkyl; and: A. R⁷ and R¹² are taken together to form—(CH₂)_(o)—, where o is 1, 2 or 3; R¹¹ is hydrogen, alkyl, aralkyl,aryl, hydroxyalkyl or carboxyalkyl; R⁸ is hydrogen; R^(a), R^(b) andR^(c) are hydrogen, hydroxy,

where R^(h) is benzyl or t-butyl, and where R^(f) is hydrogen or methyl;and R⁶ is hydrogen, C₁₋₄ alkyl, C₂₋₄ hydroxyalkyl, C₂₋₄ carboxyalkyl,C₂₋₄ aminoalkyl, dimethylamino(C₂₋₈)alkyl, or methylamino(C₂₋₈)alkyl; orB. R¹¹ is hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl or carboxyalkyl;R⁸ and R¹² are taken together to form —CH₂—CH₂—(CH₂)_(p)—, where p is 1,2 or 3; R⁷ is hydrogen; and R^(a), R^(b) and R^(c) are hydrogen,hydroxy,

where R^(h) is benzyl or t-butyl, and where R^(f) is hydrogen or methyl;and R⁶ is hydrogen, C₁₋₄ alkyl, C₂₋₄ hydroxyalkyl, C₂₋₄ carboxyalkyl,C₂₋₄ aminoalkyl, dimethylamino(C₂₋₈)alkyl, or methylamino(C₂₋₈)alkyl.23. A pharmaceutical composition for inhibiting proteolysis in a mammal,comprising an amount of a compound of any one of claims 1, 14, 15, 16,18, 20 or 21 effective to inhibit proteolysis, and a pharmaceuticallyacceptable carrier or diluent.
 24. The pharmaceutical composition ofclaim 23, comprising an amount of said compound effective to inhibit atrypsin-like protease.
 25. A method of inhibiting proteolysis in mammal,comprising administering to the mammal a composition of claim
 23. 26.The method of claim 25, wherein a trypsin-like protease is inhibited.27. A method of treating pancreatitis, thrombosis, ischemia, stroke,restenosis, emphysema or inflammation in a mammal, comprisingadministering to the mammal a composition of claim
 23. 28. A method ofinhibiting thrombin-induced platelet aggregation and clotting offibrinogen in plasma, comprising administering to the mammal acomposition of claim
 23. 29. A method for inhibiting thrombin in bloodcomprising adding to the blood a compound of claim
 1. 30. A method forinhibiting formation of blood platelet aggregates in blood comprisingadding to the blood a compound of claim
 1. 31. A method for inhibitingthrombus formation in blood comprising adding to the blood a compound ofclaim
 1. 32. In a device used in blood collection, blood circulation,and blood storage wherein said device includes an effective amount of athrombin inhibiting compound or macromolecule as an anticoagulant,either embedded in, or physically linked to, one or more materials thatform the structure of said device, the improvement comprising employingas said thrombin inhibitor one or more compounds as claimed in claim 1.33. The device of claim 32, wherein said device is a catheter, blooddialysis machine, blood collection syringe, blood collection tube, bloodline or extracorporeal blood circuit.
 34. The device of claim 32,wherein said device is a stent that can be surgically inserted into amammal.
 35. A process for preparing an aminoguanidine compound of claim1, comprising reacting an aminoguanidine of the formula

wherein R⁹, R^(a), R^(b) and R^(c) are defined in claim 1, with acarbonyl-containing compound of the formula

wherein R¹-R⁴, Z, Y, n, m, R⁷, R⁸, R¹¹ and R¹² are defined in claim 1 toform an amidinohydrazone, and thereafter selectively reducing thehydrazone carbon to nitrogen double bond of the amidinohydrazone. 36.The process of claim 35, wherein the aminoguanidine of Formula VII isprovided as a hydrochloride, acetate or nitrate salt.
 37. The process ofclaim 35, wherein the reaction is conducted at ambient temperature usingan alcohol as a solvent.
 38. The process of claim 35, wherein an acid isadded to the reaction mixture.
 39. A process for preparing analkoxyguanidine compound of claim 1, comprising reacting an alkoxyaminecompound of the formula

wherein R¹-R⁴, Z, Y, n, m, R⁷, R⁸, R¹¹ and R¹² are defined in claim 1,with a guanidinylating reagent.
 40. The process of claim 39, whereinsaid guanidinylating reagent is aminoiminosulfonic acid, optionallysubstituted 1H-pyrazole-1-carboxamidines, orN,N′-bis(tert-butoxycarbonyl)S-methyl isothiourea.
 41. A compound ofclaim 1, which is1-[[5-methyl-3-(2-methylsulfonylphenylsulfonyloxy)phenoxy]methyl]cyclopropylmethoxyguanidinehydrochloride.
 42. A compound of claim 1, which is1-[[5-methyl-3-(2-methylsulfonylphenylsulfonyloxy)phenoxy]methyl]cyclopropylmethoxyguanidineof a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.